Stereochemically defined polypropionates and methods for making and using the same

ABSTRACT

The present invention relates to stereochemically defined polypropionates and methods for preparing and using the same. The stereochemically defined polypropionates may be useful in the synthesis of natural products and/or natural product-like libraries.

RELATED APPLICATION INFORMATION

This application claims the benefit of and priority to U.S. ProvisionalApplication Ser. No. 62/032,757, filed Aug. 4, 2014, the disclosure ofwhich is hereby incorporated by reference herein in its entirety.

FIELD

The present invention relates to stereochemically definedpolypropionates and methods for preparing and using the same. Thestereochemically defined polypropionates may be useful in the synthesisof natural products and/or natural product-like libraries.

BACKGROUND

Biologically active natural products have played a key role in theelucidation of cellular processes and biological mechanisms, and havebeen fruitful sources of therapeutic agents for many decades. Nearlyhalf of the new chemical entities introduced in drug discovery between1981 and 2002 were natural products or semi-synthetic analogs of naturalproducts. (Vasilevich, N. I., et al., J. Med. Chem. 2012, 55,7003-7009.) Polypropionate tetrads and pentads comprise a corestructural element of many biologically active natural products.

SUMMARY

The present invention provides stereochemically defined polypropionates,including stereochemically defined pentads and tetrads, and methods forpreparing and using the same.

In some embodiments provided is a compound of Formula II′, III′, IV′,V′, VI′, and/or VII′ having the following structure:

wherein:

Ph is phenyl; and

R³ is each independently a hydrogen or an oxygen protecting group;

or a salt thereof.

In some embodiments, a compound of Formula II′, III′, IV′, V′, VI′,and/or VII′ can be used in a method of preparing a therapeutic.

In some embodiments, provided is a compound of Formula II, III, IV, V,VI, and/or VII having the following structure:

In some embodiments, the invention provides methods for preparingstereochemically defined polypropionate pentads, such as compounds ofFormulas II′, II, III′, III, V′, V, VI′, and VI, and stereochemicallydefined polypropionate tetrads, such as compounds of Formulas IV′, IV,VII′, and VII, from a compound of Formula I having the followingstructure:

In certain embodiments, a compound of Formula II′, II, III′, III, IV′,and/or IV is prepared from an enantiomerically pure compound of FormulaIa having the following structure:

In some embodiments, a compound of Formula V′, V, VI′, VI, VII′, and/orVII is prepared from an enantiomerically pure compound of Formula Ibhaving the following structure:

In some embodiments, methods for preparing compounds of Formulas Ia andIb are provided. In some embodiments, compounds of Formulas Ia and Ibare prepared in optically active form.

In some embodiments, compounds of Formulas Ia and/or Ib are prepared byoxidizing a compound of Formula 1 having the following structure:

In certain embodiments, a compound of Formula Ia or Ib is prepared byoxidizing an optically active compound of Formula 1A or 1B,respectively, having the following structure:

In some embodiments, compounds of Formulas 1A and/or 1B can be obtainedby resolving a mixture of compounds of Formulas 1A and 1B. In someembodiments, the resolution compounds of Formulas 1A and 1B can beachieved by selective crystallization and/or selective precipitation ofa mixture of diastereomeric salts of Formulas 1A and 1B. In someembodiments, the mixture of diastereomeric salts of Formulas 1A and 1Bcan be obtained by forming a mixture of esters of Formulas 1A and 1Bhaving free carboxylate groups, and then treating the mixture of estersof Formulas 1A and 1B having free carboxylate groups with a chiralamine-containing compound. In some embodiments, the mixture of esters ofFormulas 1A and 1B having free carboxylate groups is obtained bytreating a mixture of Formulas 1A and 1B with phthalic anhydride, toform a mixture of phthalates of Formulas 2A and 2B.

In some embodiments, the mixture of phthalates of Formulas 2A and 2B isreacted with a chiral amine-containing compound to produce a mixture ofdiastereomeric salts. In some embodiments, the chiral amine is anenantiomer of α-methylbenzylamine. In some embodiments, the mixture ofFormulas 2A and 2B is reacted with (R)-α-methylbenzylamine. In someembodiments, the mixture of Formulas 2A and 2B is reacted with(S)-α-methylbenzylamine.

In some embodiments, the mixture of diastereomeric salts is resolved byselective crystallization, or selective crystallization followed byrecrystallization. In some embodiments, the mixture of Formulas 2A and2B is treated with (S)-α-methylbenzylamine, and one of thediastereomeric salts is removed by filtration after it precipitates.

In some embodiments, a process for resolving enantiomers of a compoundof Formula 1, is provided, the method comprising the steps of:

reacting the racemic compound of Formula 1 with phthalic anhydride toform a racemic mixture of phthalates of Formulas 2A and 2B having thestructure:

reacting the racemic mixture of phthalates of Formulas 2A and 2B with afirst chiral amine in a solvent to form a pair of diastereomeric saltsthereof in a solution;

precipitating a first diastereomeric salt of the pair of diastereomericsalts from the solution to provide an isolated first diasteriomeric saltand an second diastereomeric salt; and

forming the enantiomers of the compound of Formula 1 from the isolatedfirst diastereomeric salt and the second diastereomeric salt, therebyresolving the enantiomers of the compound of Formula 1.

In some embodiments, provided is a compound of Formula 1′:

wherein:

R is hydrogen or —C(O)R¹, and

R¹ is selected from the group consisting of C₁-C₈alkyl, C₁-C₈alkenyl,aryl, and heteroaryl, R¹ may be unsubstituted or substituted from 1 to 3times with independently selected C₁-C₆alkyl, hydroxy,hydroxyC₁-C₆alkyl, methoxy, methoxyC₁-C₆alkyl, halo, haloC₁-C₆alkyl,—C(O)NH₂, —NHCOOC₁-C₆alkyl, or —COOH group(s);

or a salt thereof.

In certain embodiments, provided is a compound of Formula 1 having thefollowing structure:

In some embodiments, a process for preparing a compound of Formula 1 isprovided, the method comprising the steps of:

reacting 6,8-dimethyl-3,9-dioxatricyclo[3.3.1.0^(2,4)]nonan-7-one with areducing agent to form an intermediate having the following structure:

and

reacting the intermediate with an acid to form the compound of Formula1.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows exemplary natural products and illustrates portionscorresponding to a compound of Formula II or IV.

DETAILED DESCRIPTION

Compounds of this invention include those described generally herein,and are further illustrated by the embodiments, sub-embodiments, andspecies disclosed herein. As used herein, the following definitionsshall apply unless otherwise indicated.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as those illustratedgenerally herein, or as exemplified by particular classes, subclasses,and species of the invention. In general, the term “substituted” refersto the replacement of a hydrogen atom in a given structure with aspecified substituent. Unless otherwise indicated, a substituted groupmay have a substituent at each substitutable position of the group, andwhen more than one position in any given structure may be substitutedwith more than one substituent selected from a specified group, thesubstituent may be either the same or different at every position.Combinations of substituents envisioned by this invention are preferablythose that result in the formation of stable or chemically feasiblecompounds.

“Isomers” refer to compounds having the same number and kind of atomsand hence the same molecular weight, but differing with respect to thearrangement or configuration of the atoms.

“Stereoisomers” refer to isomers that differ only in the arrangement ofthe atoms in space.

“Diastereoisomers” or “diastereomers” and grammatical variants thereof,as used herein, refer to stereoisomers that are not mirror images ofeach other.

“Enantiomers” and grammatical variants thereof, as used herein, refer tostereoisomers that are non-superimposable mirror images of one another.

Enantiomers include “enantiomerically pure” isomers that comprisesubstantially a single enantiomer, for example, greater than or equal to90%, 92%, 95%, 98%, or 99%, or equal to 100% of a single enantiomer.

“Enantiomerically pure” as used herein refers a compound that comprisessubstantially a single enantiomer, for example, greater than or equal to90%, 92%, 95%, 98%, or 99%, or equal to 100% of a single enantiomer. Insome embodiments, a composition may comprise a compound that isenantiomerically pure.

“Stereomerically pure” as used herein means a compound or compositionthereof that comprises one stereoisomer of a compound and issubstantially free of other stereoisomers of that compound. For example,a stereomerically pure composition of a compound having one chiralcenter will be substantially free of the opposite enantiomer of thecompound. A stereomerically pure composition of a compound having twochiral centers will be substantially free of diastereomers, andsubstantially free of the enantiomer, of the compound. A typicalstereomerically pure compound comprises greater than about 80% by weightof one stereoisomer of the compound and less than about 20% by weight ofother stereoisomers of the compound, more preferably greater than about90% by weight of one stereoisomer of the compound and less than about10% by weight of the other stereoisomers of the compound, even morepreferably greater than about 95% by weight of one stereoisomer of thecompound and less than about 5% by weight of the other stereoisomers ofthe compound, and most preferably greater than about 97% by weight ofone stereoisomer of the compound and less than about 3% by weight of theother stereoisomers of the compound. See, e.g., U.S. Pat. No. 7,189,715.

“R” and “S” as terms describing isomers are descriptors of thestereochemical configuration at an asymmetrically substituted carbonatom. The designation of an asymmetrically substituted carbon atom as“R” or “S” is done by application of the Cahn-Ingold-Prelog priorityrules, as are well known to those skilled in the art, and described inthe International Union of Pure and Applied Chemistry (IUPAC) Rules forthe Nomenclature of Organic Chemistry. Section E, Stereochemistry.

“Enantiomeric excess” (ee) of an enantiomer is [(the mole fraction ofthe major enantiomer) minus (the mole fraction of the minorenantiomer)]×100.

“Stable”, as used herein, refers to compounds that are not substantiallyaltered when subjected to conditions to allow for their production,detection, and preferably their recovery, purification, and use for oneor more of the purposes disclosed herein. In some embodiments, a stablecompound or chemically feasible compound is one that is notsubstantially altered when kept at a temperature of 40° C. or less, inthe absence of moisture or other chemically reactive conditions, for atleast a week.

“Refluxing” as used herein refers to a technique in which vapors from aboiling liquid are condensed and returned to the mixture from which itcame, typically by boiling the liquid in a vessel attached to acondenser.

“Powdered iron” or “iron powder” is iron having an average particle sizeof less than 0.1, 0.5, 1, 5, 10, 20, 50, 250, 500 or 1000 μm. Particlesize can be measured using methods known in the art, e.g., mesh sizing,laser diffraction, etc.

“Zinc dust” is zinc having an average particle size of less than 0.001,0.05, 0.1, 0.5, 1, 5, 10, 15 or 20 μm. “Zinc powder” is zinc having anaverage particle size of less than 200, 175, 150, 125, or 100 μm.Particle size can be measured using methods known in the art, e.g., meshsizing, laser diffraction, etc.

An “organic” compound as used herein is a compound that contains carbon.Similarly, an “organic solvent” is a compound containing carbon that isuseful as a solvent. An “inorganic” compound is a compound notcontaining carbon.

“Mineral acid” as used herein is the acid of an inorganic compound.Examples include, but are not limited to, hydrochloric acid (HCl),nitric acid (HNO₃), phosphoric acid (H₃PO₄), sulfuric acid (H₂SO₄),boric acid (B(OH)₃), hydrofluoric acid (HF), hydrobromic acid (HBr),perchoric acid (HClO₄), etc.

A “hydrocarbon” is an organic compound consisting of carbon and hydrogenatoms. Examples of hydrocarbons useful as “hydrocarbon solvents”include, but are not limited to, an “aromatic hydrocarbon solvent” suchas benzene, toluene, xylenes, etc., and an “aliphatic hydrocarbonsolvent” such as pentane, hexane, heptane, etc.

An “amine” or “amine base” as used herein refers to an organic compoundhaving a basic nitrogen atom (R—NR′R″), and may be a primary (R—NH₂),secondary (R—NHR′) or tertiary (R—NR′R″) amine.

A “strong base” as used herein is a compound that is capable ofdeprotonating very weak acids. Examples of strong bases include, but arenot limited to, hydroxides, alkoxides, and ammonia.

A “hydroxide” is the commonly known diatomic anion OH⁻, or a saltthereof (typically an alkali metal or alkaline earth metal saltthereof). Examples of hydroxides include, but are not limited to, sodiumhydroxide (NaCl), potassium hydroxide (KOH), lithium hydroxide (LiOH),and calcium hydroxide (CaOH).

An “alkoxide” is RO⁻, the conjugate base of an alcohol. Examplesinclude, but are not limited to, methoxide, ethoxide, and propoxide.

“Ar” or “aryl” refer to an aromatic carbocyclic moiety having one ormore closed rings. Examples include, without limitation, phenyl,naphthyl, anthracenyl, phenanthracenyl, biphenyl, and pyrenyl.

“Heteroaryl” refers to a cyclic moiety having one or more closed rings,with one or more heteroatoms (for example, oxygen, nitrogen or sulfur)in at least one of the rings, wherein at least one of the rings isaromatic, and wherein the ring or rings may independently be fused,and/or bridged. Examples include, without limitation phenyl, thiophenyl,triazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl,isoquinolinyl, indolyl, furyl, thienyl, pyrazolyl, quinoxalinyl,pyrrolyl, indazolyl, thieno[2,3-c]pyrazolyl, benzofuryl,pyrazolo[1,5-a]pyridyl, thiophenylpyrazolyl, benzothienyl,benzothiazolyl, thiazolyl, 2-phenylthiazolyl, and isoxazolyl.

“Alkyl” or “alkyl group,” as used herein, means a straight-chain (i.e.,unbranched), branched, or cyclic hydrocarbon chain that is completelysaturated. In some embodiments, alkyl groups contain 1, 2, or 3, to 4,5, 6, 7, or 8 carbon atoms (e.g., C₁₋₄, C₂₋₄, C₃₋₄, C₁₋₅, C₂₋₅, C₃₋₅,C₁₋₆, C₂₋₆, C₃₋₆, C₂₋₇, C₁₋, C₄₋₈, etc.). In some embodiments, alkylgroups contain 1-8 carbon atoms. In certain embodiments, alkyl groupscontain 1-6 carbon atoms. In still other embodiments, alkyl groupscontain 2-3 carbon atoms, and in yet other embodiments alkyl groupscontain 1-4 carbon atoms. In certain embodiments, the term “alkyl” or“alkyl group” refers to a cycloalkyl group, also known as carbocycle.Non-limiting examples of exemplary alkyl groups include methyl, ethyl,propyl, isopropyl, butyl, cyclopropyl and cyclohexyl.

“Alkenyl” or “alkenyl group,” as used herein, refers to a straight-chain(i.e., unbranched), branched, or cyclic hydrocarbon chain that has oneor more double bonds. In certain embodiments, alkenyl groups contain 1-8carbon atoms. In certain embodiments, alkenyl groups contain 1-6 carbonatoms. In still other embodiments, alkenyl groups contain 1-4 carbonatoms, and in yet other embodiments alkenyl groups contain 2-3 carbonatoms. According to another aspect, the term alkenyl refers to astraight chain hydrocarbon having two double bonds, also referred to as“diene.” In other embodiments, the term “alkenyl” or “alkenyl group”refers to a cycloalkenyl group. Non-limiting examples of exemplaryalkenyl groups include —CH═CH₂, —CH₂CH═CH₂ (also referred to as allyl),—CH═CH₃, —CH₂CH═CH═CH₂, —CH₂CH═CHCH₃, —CH═CH₂CH₂CH₃, —CH═CH₂CH═CH₂, andcyclobutenyl.

“Alkoxy”, or “alkylthio”, as used herein, refers to an alkyl group, aspreviously defined, attached to the principal carbon chain through anoxygen (“alkoxy”) or sulfur (“alkylthio”) atom.

“Methylene”, “ethylene”, and “propylene” as used herein refer to thebivalent moieties —CH₂—, —CH₂CH₂—, and —CH₂CH₂CH₂—, respectively.

“Ethenylene”, “propenylene”, and “butenylene” as used herein refer tothe bivalent moieties —CH═CH—, —CH═CHCH₂—, —CH₂CH═CH—, —CH═CHCH₂CH₂—,—CH₂CH═CH₂CH₂—, and —CH₂CH₂CH═CH—, where each ethenylene, propenylene,and butenylene group can be in the cis or trans configuration. Incertain embodiments, an ethenylene, propenylene, or butenylene group canbe in the trans configuration.

“Alkylidene” refers to a bivalent hydrocarbon group formed by mono ordialkyl substitution of methylene. In certain embodiments, an alkylidenegroup has 1-6 carbon atoms. In other embodiments, an alkylidene grouphas 2-6, 1-5, 2-4, or 1-3 carbon atoms. Such groups include propylidene(CH₃CH₂CH═), ethylidene (CH₃CH═), and isopropylidene (CH₃(CH₃)CH═), andthe like.

“Alkenylidene” refers to a bivalent hydrocarbon group having one or moredouble bonds formed by mono or dialkenyl substitution of methylene. Incertain embodiments, an alkenylidene group has 2-6 carbon atoms. Inother embodiments, an alkenylidene group has 2-6, 2-5, 2-4, or 2-3carbon atoms. According to one aspect, an alkenylidene has two doublebonds. Exemplary alkenylidene groups include CH₃CH═C═, CH₂═CHCH═,CH₂═CHCH₂CH═, and CH₂═CHCH₂CH═CHCH═.

“C₁₋₆ alkyl ester or amide” refers to a C₁₋₆ alkyl ester or a C₁₋₆ alkylamide where each C₁₋₆ alkyl group is as defined above. Such C₁₋₆ alkylester groups are of the formula (C₁₋₆ alkyl)OC(═O)— or (C₁₋₆alkyl)C(═O)O—. Such C₁₋₆ alkyl amide groups are of the formula (C₁₋₆alkyl)NHC(═O)— or (C₁₋₆ alkyl)C(═O)NH—.

“C₂₋₆ alkenyl ester or amide” refers to a C₂₋₆ alkenyl ester or a C₂₋₆alkenyl amide where each C₂₋₆ alkenyl group is as defined above. SuchC₂₋₆ alkenyl ester groups are of the formula (C₂₋₆ alkenyl)OC(═O)— or(C₂₋₆ alkenyl)C(═O)O—. Such C₂₋₆ alkenyl amide groups are of the formula(C₂₋₆ alkenyl)NHC(═O)— or (C₂₋₆ alkenyl)C(═O)NH—.

“Halo” refers to fluoro, chloro, bromo or iodo.

“Haloalkyl” refers to an alkyl group substituted with one or more haloatoms (e.g., fluoro, chloro, bromo, and/or iodo atoms). For example,“fluoromethyl” refers to a methyl group substituted with one or morefluoro atoms (e.g., monofluoromethyl, difluoromethyl, andtrifluoromethyl).

“Hydroxyalkyl” refers to an alkyl group substituted with a hydroxylgroup (—OH).

“Fluoromethoxy” as used herein, refers to a fluoromethyl group, aspreviously defined, attached to the principal carbon chain through anoxygen atom.

“Protecting group” as used herein, is meant that a particular functionalmoiety, e.g., O, S, or N, is temporarily blocked so that a reaction canbe carried out selectively at another reactive site in a multifunctionalcompound. For example, in certain embodiments, as detailed herein,certain exemplary oxygen protecting groups are utilized. Oxygenprotecting groups include, but are not limited to, groups bonded to theoxygen to form an ether, such as methyl, substituted methyl (e.g., Trt(triphenylmethyl), MOM (methoxymethyl), MTM (methylthiomethyl), BOM(benzyloxymethyl), PMBM or MPM (p-methoxybenzyloxymethyl)), substitutedethyl (e.g., 2-(trimethylsilyl)ethyl), benzyl, substituted benzyl (e.g.,para-methoxybenzyl), silyl (e.g., TMS (trimethylsilyl), TES(triethylsilyl), TIPS (triisopropylsilyl), TBDMS (t-butyldimethylsilyl),tribenzylsilyl, TBDPS (t-butyldiphenyl silyl),2-trimethylsilylprop-2-enyl, t-butyl, tetrahydropyranyl, allyl, etc.

In some embodiments, a compound of the present invention may be providedas a salt, such as a pharmaceutically acceptable salt. Pharmaceuticallyacceptable salts are salts that retain the desired biological activityof the parent compound and do not impart undesired toxicologicaleffects. Specific examples of pharmaceutically acceptable salts includeinorganic acid salts (such as sulfates, nitrates, perchlorates,phosphates, carbonates, bicarbonates, hydrofluorides, hydrochlorides,hydrobromides and hydroiodides), organic carboxylates (such as acetates,oxalates, maleates, tartrates, fumarates and citrates), organicsulfonates (such as methanesulfonates, trifluoromethanesulfonates,ethanesulfonates, benzenesulfonates, toluenesulfonates andcamphorsulfonates), amino acid salts (such as aspartates andglutamates), quaternary amine salts, alkali metal salts (such as sodiumsalts and potassium salts) and alkali earth metal salts (such asmagnesium salts and calcium salts).

Unless indicated otherwise, nomenclature used to describe chemicalgroups or moieties as used herein follow the convention where, readingthe name from left to right, the point of attachment to the rest of themolecule is at the right-hand side of the name. For example, the group“(C₁₋₃ alkoxy)C₁₋₃ alkyl,” is attached to the rest of the molecule atthe alkyl end. Further examples include methoxyethyl, where the point ofattachment is at the ethyl end, and methylamino, where the point ofattachment is at the amine end.

Unless indicated otherwise, where a mono or bivalent group is describedby its chemical formula, including one or two terminal bond moietiesindicated by “-,” it will be understood that the attachment is read fromleft to right.

Unless otherwise stated, structures depicted herein are meant to includeall enantiomeric, diastereomeric, and geometric (or conformational)forms of the structure; for example, the R and S configurations for eachasymmetric center, (Z) and (E) double bond isomers, and (Z) and (E)conformational isomers. Therefore, single stereochemical isomers as wellas enantiomeric, diastereomeric, and geometric (or conformational)mixtures of the present compounds are within the scope of the invention.Unless otherwise stated, all tautomeric forms of the compounds of theinvention are within the scope of the invention.

Additionally, unless otherwise stated, structures depicted herein arealso meant to include compounds that differ only in the presence of oneor more isotopically enriched atoms. For example, compounds having thepresent structures except for the replacement of hydrogen by deuteriumor tritium, or the replacement of a carbon by a ³C- or ¹⁴C-enrichedcarbon are within the scope of this invention. Such compounds areuseful, for example, as analytical tools or probes in biological assays.

Provided herein according to some embodiments is a compound of Formula1′:

wherein:

R is hydrogen or —C(O)R¹, and

R¹ is selected from the group consisting of C₁-C₈alkyl, C₁-C₈alkenyl,aryl, and heteroaryl, R¹ may be unsubstituted or substituted from 1 to 3times with independently selected C₁-C₆alkyl, hydroxy,hydroxyC₁-C₆alkyl, methoxy, methoxyC₁-C₆alkyl, halo, haloC₁-C₆alkyl,—C(O)NH₂, —NHCOOC₁-C₆alkyl, or —COOH group(s);

or a salt thereof.

In some embodiments, a compound of Formula 1′ has the stereochemistry ofFormula 1A′:

In some embodiments, a compound of Formula I has the stereochemistry ofFormula IB:

According to some embodiments, R in a compound of Formula 1′ is ahydrogen and the compound has a structure of Formula 1:

or a salt thereof.

In some embodiments, a compound of Formula 1 has the stereochemistry ofFormula 1A:

In some embodiments, a compound of Formula 1 has the stereochemistry ofFormula 1B:

According to some embodiments, R in a compound of Formula 1′ is —C(O)R¹or a salt thereof. In certain embodiments, in a compound of Formula 1′,R is —C(O)R¹ and R¹ is substituted with —COOH, or a salt thereof.

Provided according to further embodiments of the present invention is acompound of Formula 2:

or a salt thereof.

In some embodiments, a compound of Formula 2 has the stereochemistry ofFormula 2A:

In some embodiments, a compound of Formula 2 has the stereochemistry ofFormula 2B:

In some embodiments, a process for preparing a compound of Formula 1 isprovided. The process may comprise reacting6,8-dimethyl-3,9-dioxatricyclo[3.3.1.0^(2,4)]nonan-7-one with a reducingagent to form an intermediate having the following structure:

reacting the intermediate with an acid to form the compound of Formula1.

Exemplary reducing agents that may be used in preparing a compound ofFormula 1 include, but are not limited to, hydrides, such as sodiumborohydride, potassium borohydride, lithium borohydride, lithiumaluminum hydride, and sodium cyanoborohydride. In some embodiments, thereducing agent may be sodium borohydride.

Exemplary acids that may be used in preparing a compound of Formula 1include, but are not limited to, hydrochloric acid, hydrofluoric acid,hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, citricacid, glycolic acid, formic acid, oxalic acid, boric acid, and/or aceticacid. In some embodiments, the acid may be hydrochloric acid.

According to some embodiments, a process for resolving enantiomers ofthe compound of Formula 1 is provided. The process may be a process forresolving a mixture of compounds of Formulas 1A and 1B. In someembodiments, the resolution compounds of Formulas 1A and 1B may beachieved by selective crystallization and/or selective precipitation ofa mixture of diastereomeric salts of Formulas 1A and 1B. In someembodiments, the mixture of diastereomeric salts of Formulas 1A and 1Bmay be obtained by forming a mixture of esters of Formulas 1A and 1Bhaving free carboxylate groups, and then by treating the mixture ofesters of Formulas 1A and 1B having free carboxylate groups with achiral amine-containing compound (i.e., a chiral amine), such as, forexample, α-methylbenzylamine.

In some embodiments, a process for resolving enantiomers of the compoundof Formula I may comprise reacting the racemic compound of Formula 1:

with phthalic anhydride to form a racemic mixture of phthalates ofFormulas 2A and 2A:

The racemic mixture of phthalates of Formula 2 may be reacted with afirst chiral amine in a solvent to form a pair of diastereomeric saltsthereof in a solution, and a first diastereomeric salt of the pair ofdiastereomeric salts may be precipitated from the solution to provide anisolated first diastereomeric salt and an second diastereomeric salt.Enantiomers of the compound of Formula 1 may then be formed from theisolated first diastereomeric salt and the second diastereomeric salt,thereby resolving the enantiomers of the compound of Formula 1.

In some embodiments, prior to reacting the racemic mixture of phthalatesof Formula 2 with the first chiral amine in the solvent to form the pairof diastereomeric salts thereof in the solution, the racemic mixture ofphthalates of Formula 2 may be dissolved in the solvent. In someembodiments, the racemic mixture of phthalates of Formula 2 may bedissolved in the solvent at a volume ratio in a range of about 1:12 toabout 1:20 (phthalates:solvent), such as, but not limited to, at avolume ratio of about 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or1:20. In some embodiments, the volume ratio may be about 1:15. In someembodiments, the solvent may be acetone.

In some embodiments, the first chiral amine is (S)-α-methylbenzylamine.Reacting (S)-α-methylbenzylamine with the racemic mixture of phthalatesof Formula 2 in a solvent may precipitate the first diastereomeric saltof the pair of diastereomeric salts from the solution, thereby providingthe isolated first diastereomeric salt. In some embodiments, theisolated first diastereomeric salt may have the following structure ofFormula 2B′:

In some embodiments, a process for resolving enantiomers of the compoundof Formula 1 may comprise treating the isolated first diastereomericsalt with a base to form a first enantiomeric compound of Formula 1.Exemplary bases include, but are not limited to, sodium hydroxide,potassium hydroxide, barium hydroxide, calcium hydroxide, cesiumhydroxide, and/or alkoxides, such as, for example sodium, potassium,and/or lithium methoxide, ethoxide, propoxide, and/or n-butoxide. Insome embodiments, the isolated first diastereomeric salt may be acompound of Formula 2B′ and the first enantiomeric compound of Formula 1may be a compound of Formula 1B having the following structure:

or a salt thereof. The first diastereomeric salt may be in crystallineform. Accordingly, the process may comprise one or more crystallizationsteps (e.g., crystallizing and/or recrystallizing steps).

In some embodiments, a process for resolving enantiomers of the compoundof Formula 1 may comprise separating the first diastereomeric salt fromthe solution to separately provide the isolated first diastereomericsalt and the second diastereomeric salt. Exemplary methods of separatingwill be known to those of skill in the art and include, but are notlimited to, filtering the solution to separately provide the isolatedfirst diastereomeric salt and the second diastereomeric salt.

A process for resolving enantiomers of the compound of Formula 1 maycomprise acidifying the second diastereomeric salt to form a freephthalate. The second diastereomeric salt may have the followingstructure of Formula 2A′:

The free phthalate may be reacted with a second chiral amine to reformthe second diastereomeric salt in a solution. In some embodiments, thesecond chiral amine is (R)-α-methylbenzylamine. The seconddiastereomeric salt may be precipitated from the solution to form anisolated second diastereomeric salt. In some embodiments, the isolatedsecond diastereomeric salt may be a compound of Formula 2A′. A secondenantiomeric compound of Formula 1 may be from the isolated seconddiastereomeric salt.

In some embodiments, prior to reacting the free phthalate with thesecond chiral amine to reform the second diastereomeric salt in thesolution, the free phthalate may be dissolved in a solvent. In someembodiments, the free phthalate may be dissolved in the solvent at avolume ratio in a range of about 1:12 to about 1:20 (phthalate:solvent),such as, but not limited to, at a volume ratio of about 1:12, 1:13,1:14, 1:15, 1:16, 1:17, 1:18, 1:19, or 1:20. In some embodiments, thevolume ratio may be about 1:15. In some embodiments, the solvent may beacetone.

In some embodiments, a process for resolving enantiomers of the compoundof Formula 1 may comprise treating the isolated second diastereomericsalt with a base to form a second enantiomeric compound of Formula 1.Exemplary bases include, but are not limited to, sodium hydroxide,potassium hydroxide, barium hydroxide, calcium hydroxide, cesiumhydroxide, and/or alkoxides, such as, for example sodium, potassium,and/or lithium methoxide, ethoxide, propoxide, and/or n-butoxide. Insome embodiments, the isolated second diastereomeric salt may be acompound of Formula 2A′ and the second enantiomeric compound of Formula1 may be a compound of Formula 1A having the following structure:

In some embodiments, the second diastereomeric salt may be incrystalline form. Accordingly, the process may comprise one or morecrystallization steps (e.g., crystallizing and/or recrystallizingsteps).

Provided according to further embodiments of the present invention is acompound of Formula I having the structure:

In some embodiments, a compound of Formula I may have thestereochemistry of a compound of Formula Ia:

In some embodiments, a compound of Formula I may have thestereochemistry of a compound of Formula Ib:

According to some embodiments, a process for preparing a compound ofFormula I may be provided. The process may comprise treating a compoundof Formula 1:

with an oxidizing agent to form the compound of Formula I. Exemplaryoxidizing agents include, but are not limited to, peracetic acid,perbenzoic acid, m-chloroperbenzoic acid, perphthalic acid, performicacid, trifluoroperacetic acid, sulfur trioxide pyridine complex,hydrogen peroxide, pyridinium dichromate (PDC), and/or pyridiniumchlorochromate (PCC). In some embodiments, the oxidizing agent may bem-chloroperbenzoic acid. In some embodiments, the oxidizing agent may bea sulfur trioxide pyridine complex.

A catalyst may optionally be present during the treatment of a compoundof Formula 1 with an oxidizing agent to form a compound of Formula I.Exemplary catalysts include, but are not limited to,2,2,6,6-tetramethyl-1-piperidinyloxy,4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy,4-(2-chloroacetamido)-2,2,6,6-tetramethyl-1-piperidinyloxy, and/or4-(acetylamino)-2,2,6,6-tetramethyl-piperidinyloxy. In some embodiments,the catalyst may be 2,2,6,6-tetramethyl-1-piperidinyloxy. In certainembodiments, the catalyst may be 2,2,6,6-tetramethyl-1-piperidinyloxyand the oxidizing agent may be m-chloroperbenzoic acid.

In some embodiments, a process for preparing a compound of Formula I mayform an intermediate ketone having the following structure of FormulaIa″:

In some embodiments, a process for preparing a compound of Formula I mayform an intermediate ketone having the following structure of FormulaIb″:

In some embodiments, a compound of Formula 1 may be reacted with anoxidizing agent, such as, for example, a sulfur trioxide pyridinecomplex, to form the intermediate ketone of Formula Ia″ and/or FormulaIb″. The intermediate ketone of Formula Ia″ and/or Formula Ib″ may bethen reacted with an oxidizing agent, such as, for example,m-chloroperbenzoic acid, optionally in the presence of a catalyst.

In some embodiments, a process for preparing a compound of Formula I maycomprise treating a compound of Formula 1a:

with an oxidizing agent, optionally in the presence of a catalyst, toform a compound of Formula Ia:

In some embodiments, a process for preparing a compound of Formula I maycomprise treating a compound of Formula 1b:

with an oxidizing agent, optionally in the presence of a catalyst, toform a compound of Formula Ib:

According to some embodiments, provided is a compound of Formula II′,III′, IV′, V′, VI′, and/or VII′ having the following structure:

wherein:

Ph is phenyl; and

R³ is each independently a hydrogen or an oxygen protecting group;

or a salt thereof.

In some embodiments, at least one R³ is hydrogen in a compound ofFormula II, III′, IV′, V′, VI′, or VII′. In some embodiments, at leastone R³ is an oxygen protecting group in a compound of Formula II′, III′,IV′, V′, VI′, or VII′. In some embodiments, at least one R³ is hydrogenand at least one R³ is an oxygen protecting group in a compound ofFormula II′, III′, IV′, V′, VI′, or VII′. In some embodiments, two ormore R³ are hydrogen in a compound of Formula II′, III′, IV′, V′, VI′,or VII′. In some embodiments, two or more R³ are an oxygen protectinggroup that may be the same as or different than another R³ in a compoundof Formula II′, III′, IV′, V′, VI′, or VII′. In certain embodiments, allR³ are hydrogen in a compound of Formula II′, III′, IV′, V′, VI′, orVII′. In certain embodiments, all R³ are an oxygen protecting group thatmay be the same as or different than another R³ in a compound of FormulaII, III′, IV′, V′, VI′, or VII′.

Exemplary oxygen protecting groups include, but are not limited to,those described herein, such as Trt (triphenylmethyl), MOM(methoxymethyl), MTM (methylthiomethyl), BOM (benzyloxymethyl), PMBM orMPM (p-methoxybenzyloxymethyl)), substituted ethyl (e.g.,2-(trimethylsilyl)ethyl), benzyl, substituted benzyl (e.g.,para-methoxybenzyl), silyl (e.g., TMS (trimethylsilyl), TES(triethylsilyl), TIPS (triisopropylsilyl), TBDMS (t-butyldimethylsilyl),tribenzylsilyl, TBDPS (t-butyldiphenyl silyl),2-trimethylsilylprop-2-enyl, t-butyl, tetrahydropyranyl, and/or allyl.In some embodiments, the oxygen protecting group is triethylsilyl (TES).

In some embodiments, provided is a compound of Formula II, III, IV, V,VI, and/or VII having the following structure:

Provided in some embodiments is a method for preparing a compound ofFormula II′, II, III′, III, IV′, IV, V′, V, VI′, VI, VII′, and/or VII.Described below are exemplary processes for preparing a compound ofFormula II, III, IV, V, VI, and VII. As those skilled in the art willreadily appreciate the exemplary processes may be modified, such as bynot removing the oxygen protecting group to prepare a compound ofFormula II′, III′, IV′, V′, VI′, or VII′. Exemplary reducing agents andoxygen protecting that may be used in a method for preparing a compoundof Formula II′, II, III′, III, IV′, IV, V′, V, VI′, VI, VII′, and/or VIIinclude those described herein.

In some embodiments, a process for preparing a compound of Formula IV isprovided. A process for preparing a compound of Formula IV may compriseproviding a mixture of a dialkyl((arylsulfonyl)methyl)phosphonate and acompound of Formula I having the stereochemistry of a compound ofFormula Ia:

reacting the mixture with an alkoxide in a polar protic solvent to forma compound of Formula AAAA having the structure:

reducing the compound of Formula AAAA in the presence of a catalyst toform a compound of Formula BBBB having the structure:

reacting the compound of Formula BBBB with an oxygen protecting group toform a protected ester;

reacting the protected ester with a reducing agent to form a protectedalcohol;

reacting the protected alcohol with a halogen to form a halogenatedcompound;

dehalogenating the halogenated compound to form a compound of FormulaKKKK having the structure:

wherein:

Ph is a phenyl group; and

R² is an oxygen protecting group; and

removing the oxygen protecting group of the compound of Formula KKKK toform the compound of Formula IV.

In some embodiments, a process for preparing a compound of Formula IIImay be provided. A process for preparing a compound of Formula III maycomprise providing a mixture of adialkyl((arylsulfonyl)methyl)phosphonate and a compound of Formula Ihaving the stereochemistry of a compound of Formula Ia:

reacting the mixture with an alkoxide in a polar protic solvent to forma compound of Formula AAAA having the structure:

reacting the compound of Formula AAAA with an oxygen protecting group toform a protected ester;

reacting the protected ester with a reducing agent to form a protectedalcohol;

reacting the protected alcohol with a halogen to form a halogenatedcompound;

dehalogenating the halogenated compound to form a compound of FormulaLLLL having the structure:

wherein:

Ph is a phenyl group; and

R² is an oxygen protecting group; and

reacting the compound of Formula LLLL with a methyllithium-lithiumbromide complex to form the compound of Formula III.

In some embodiments, a process for preparing a compound of Formula IImay be provided. A process for preparing a compound of Formula II maycomprise providing a mixture of adialkyl((arylsulfonyl)methyl)phosphonate and a compound of Formula Ihaving the stereochemistry of a compound of Formula Ia:

reacting the mixture with an alkoxide in a polar protic solvent to forma compound of Formula AAAA having the structure:

reacting the compound of Formula AAAA with an oxygen protecting group toform a protected ester;

reacting the protected ester with a reducing agent to form a protectedalcohol;

reacting the protected alcohol with a halogen to form a halogenatedcompound;

dehalogenating the halogenated compound to form a compound of FormulaLLLL having the structure:

wherein:

Ph is a phenyl group; and

R² is an oxygen protecting group; and

reacting the compound of Formula LLLL with methyllithium in the presenceof copper to form the compound of Formula II.

In some embodiments, a process for preparing a compound of Formula VIImay be provided. A process for preparing a compound of Formula VII maycomprise providing a mixture of adialkyl((arylsulfonyl)methyl)phosphonate and a compound of Formula Ihaving the stereochemistry of a compound of Formula Ib:

reacting the mixture with an alkoxide in a polar protic solvent to forma compound of Formula MMMM having the structure:

reducing the compound of Formula MMMM in the presence of a catalyst toform a compound of Formula NNNN having the structure:

reacting the compound of Formula NNNN with an oxygen protecting group toform a protected ester;

reacting the protected ester with a reducing agent to form a protectedalcohol;

reacting the protected alcohol with a halogen to form a halogenatedcompound;

dehalogenating the halogenated compound to form a compound of FormulaOOOO having the structure:

wherein:

Ph is a phenyl group; and

R² is an oxygen protecting group; and

removing the oxygen protecting group of the compound of Formula OOOO toform the compound of Formula VII.

In some embodiments, a process for preparing a compound of Formula VImay be provided. A process for preparing a compound of Formula VI maycomprise providing a mixture of adialkyl((arylsulfonyl)methyl)phosphonate and a compound of Formula Ihaving the stereochemistry of a compound of Formula Ib:

reacting the mixture with an alkoxide in a polar protic solvent to forma compound of Formula MMMM having the structure:

reacting the compound of Formula MMMM with an oxygen protecting group toform a protected ester;

reacting the protected ester with a reducing agent to form a protectedalcohol;

reacting the protected alcohol with a halogen to form a halogenatedcompound;

dehalogenating the halogenated compound to form a compound of FormulaPPPP having the structure:

wherein:

Ph is a phenyl group; and

R² is an oxygen protecting group; and

reacting the compound of Formula PPPP with a methyllithium-lithiumbromide complex to form the compound of Formula VI.

In some embodiments, a process for preparing a compound of Formula V maybe provided. A process for preparing a compound of Formula V maycomprise providing a mixture of adialkyl((arylsulfonyl)methyl)phosphonate and a compound of Formula Ihaving the stereochemistry of a compound of Formula Ib:

reacting the mixture with an alkoxide in a polar protic solvent to forma compound of Formula MMMM having the structure:

reacting the compound of Formula MMMM with an oxygen protecting group toform a protected ester;

reacting the protected ester with a reducing agent to form a protectedalcohol;

reacting the protected alcohol with a halogen to form a halogenatedcompound;

dehalogenating the halogenated compound to form a compound of FormulaPPPP having the structure:

wherein:

Ph is a phenyl group; and

R² is an oxygen protecting group; and

reacting the compound of Formula PPPP with methyllithium in the presenceof copper to form the compound of Formula V.

Any suitable dialkyl((arylsulfonyl)methyl)phosphonate may be used in aprocess for preparing a compound of Formula II, III, IV, V, VI, or VII.In some embodiments, in a process for preparing a compound of FormulaII, III, IV, V, VI, or VII, the dialkyl((arylsulfonyl)methyl)phosphonatemay be dimethyl((phenylsulfonyl)methylphosphonate.

In some embodiments, in a process for preparing a compound of FormulaII, III, IV, V, VI, or VII, the alkoxide may be present in an excess ofabout 2 to about 3 equivalents, such as, for example, in an excess ofabout 2, 2.1, 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, or 3 equivalents.Any suitable alkoxide may be used in a process for preparing a compoundof Formula II, III, IV, V, VI, or VII. In some embodiments, the alkoxideis a sodium alkoxide, such as, but not limited to, sodium methoxide andsodium ethoxide.

Any suitable polar protic solvent may be used in a process for preparinga compound of Formula II, III, IV, V, VI, or VII. In some embodiments,in a process for preparing a compound of Formula II, III, IV, V, VI, orVII, the polar protic solvent is an alcohol, such as, but not limitedto, methanol and ethanol. Any suitable alcohol may be used in a processfor preparing a compound of Formula II, III, IV, V, VI, or VII. In someembodiments, the polar protic solvent and alkoxide used in a process forpreparing a compound of Formula II, III, IV, V, VI, or VII may becompatible. For example, in some embodiments, the alkoxide may be sodiummethoxide and the polar protic solvent may be methanol.

According to some embodiments of the present invention, a method ofusing a compound of Formula II′, III′, IV′, V′, VI′, and/or VII′ isprovided. In some embodiments, a method of using a compound of FormulaII, I, IV, V, VI, and/or VII is provided.

In some embodiments, a compound of Formula II′, III′, IV′, V′, VI′,and/or VII′ may be used to prepare a natural product or an intermediatethereof. In some embodiments, a compound of Formula II, III, IV, V, VI,and/or VII may be used to prepare a natural product or an intermediatethereof. Exemplary natural products include, but are not limited to,spirangien A, spirangien B, dolabriferol, scytophycin C, zincophorin,stigmatellin, rifamycin SV, tirandamycin A, aplyronine A, aplyronine E,reidispongioloide, misakinolide, and/or mycarolide. FIG. 1 illustratesexemplary natural products and indicates areas (i.e., the boxed areas)that are consistent with a compound of Formula II or IV and/or in whicha compound of Formula II or IV may be used to prepare that portion ofthe natural product Thus, a compound of Formula II or IV may be used toprepare the shown natural products or intermediates thereof.

In some embodiments, a compound described herein, or a salt thereof, maybe useful in a method of synthesizing a fused aminodihydrothiazinederivative. In some embodiments, the compound may be a compound ofFormula II′, II, III′, III, IV′, IV, V′, V, VI, VI, VII′, and/or VII.

In some embodiments, a compound described herein, or salt thereof, maybe used to prepare a combinatorial library. In some embodiments, acompound of Formula II′, III′, IV′, V′, VI′, and/or VII′ may be used toprepare a combinatorial library. In some embodiments, a compound ofFormula II, III, IV, V, VI, and/or VII may be used to prepare acombinatorial library.

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. It should beunderstood that these examples are for illustrative purposes only andare not to be construed as limiting this invention in any manner.

Examples

General:

Column chromatography was carried out using Biotage SP4. Solvent removalwas carried out using either a Btlchii rotary evaporator or a Genevaccentrifugal evaporator. Preparative LC/MS was conducted using a Watersautopurifier and 19×100 mm XTerra 5 micron MS C18 column under acidicmobile phase condition. NMR spectra were recorded using Varian 400 MHzspectrometer.

When the term “inerted” is used to describe a reactor (e.g., a reactionvessel, flask, glass reactor, and the like) it is meant that the air inthe reactor has been replaced with an essentially moisture-free or dry,inert gas (such as nitrogen, argon, and the like). The term “equivalent”(abbreviation: eq) as used herein describes the stoichiometry (molarratio) of a reagent or a reacting compound by comparison to apre-established starting material. The term “weight” (abbreviation: wt)as used herein corresponds to the ratio of the mass of a substance or agroup of substances by comparison to the mass of a particular chemicalcomponent of a reaction or purification specifically referenced in theexamples below. The ratio is calculated as: g/g, or Kg/Kg. The term“volume” (abbreviation: vol) as used herein corresponds to the ratio ofthe volume of a given substance or a group of substances to the mass orvolume of a pre-established chemical component of a reaction orpurification. The units used in the equation involve matching orders ofmagnitude. For example, a ratio is calculated as: mL/mL, mL/g, L/L orL/Kg.

General methods and experimentals for preparing compounds of the presentinvention are set forth below. In certain cases, a particular compoundis described by way of example. However, it will be appreciated that ineach case a series of compounds of the present invention were preparedin accordance with the schemes and experimentals described below.

The following abbreviations are used herein:

Abbreviation Definition TMS Trimethylsilyl TBAF Tetrabutylammoniumfluoride NaOH Sodium hydroxide Bu₄N HSO₄ Tetrabutylammonium hydrogensulfate THF Tetrahydrofuran rt Room temperature h Hour(s) NaCl Sodiumchloride HCOOH Formic acid V Volumes wt Weights CDI1,1′-Carbonyldiimidazole DCM Dichloromethane Aq Aqueous Sat. SaturatedHCl Hydrochloric acid HRMS High Resolution Mass Spectrometry nBuLin-butyl lithium NH₄Cl Ammonium chloride MeOH Methanol EtOAc Ethylacetate NaHCO₃ Sodium bicarbonate M Molar (moles/liter) T TemperatureMTBE Methyl tert-butyl ether TLC Thin layer chromatography N Normal(equivalents per liter) iPrMgBr Isopropyl magnesium bromide LiCl Lithiumchloride NaOAc Sodium acetate NH₄OH Ammonium hydroxide HPLC Highperformance liquid chromatography ee Enantiomeric excess DMI1,3-Dimethyl-2-imidazolidinone UV Ultraviolet RRT Relative retentiontime OROT Optical rotation Bz Benzoyl T3P ® (Archimica) n-propylphosphonic acid anhydride Ph Phenyl TES Triethylsilyl

A. Preparation of Compounds of Formula 1

Compounds of Formulas 1a and 1b were prepared as shown in Scheme 1.

Synthesis and Resolution of Alcohols of Formulas 1a and 1b.

(1R,2S,4R,5S)-2,4-Dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one

To a 22 L reactor under nitrogen were charged acetonitrile (6.2 L) andsodium iodide (4420 g) at room temperature. While vigorously stirring,the suspension was treated with copper (969 g) and freshly distilledfuran (1.47 L). Then, a solution of 2,4-dibromo-3-pentanone (1247 g) inacetonitrile (1.2 L) was added maintaining the internal temperaturebelow 55° C. The resulting mixture was stirred at 45-50° C. for 4 h.After cooling to 20° C., the reaction was quenched with water (4 L) andMTBE (4 L), and the resulting mixture was stirred at 0° C. overnight.The resulting precipitate was filtered through celite 545 (2.4 kg) andsequentially washed with MTBE (1 L) and methylene chloride (4 L). Theorganic layer was separated from the filtrate, diluted with MTBE (1 L),and sequentially washed with 28% ammonium hydroxide (3.5 L) and amixture of 28% ammonium hydroxide (3 L) and water (1 L). The organiclayer was further diluted with MTBE (6.5 L), and sequentially washedwith water (2 L, containing sodium chloride (25 g)), a mixture of 28%ammonium hydroxide (1.5 L) and water (1 L), and water (4 L). The firstaqueous layer was back-extracted twice with a mixture of MTBE (3 L) andmethylene chloride (3 L). The organic layers were combined, washed twicewith a mixture of 28% ammonium hydroxide (2.5 L), water (1 L) and sodiumchloride (25 g), and then washed with water (4 L). The yellow organiclayer was concentrated under reduced pressure, and azeotroped withn-heptane (4 L). The residue was treated with n-heptane (4 L),concentrated down to ˜3 L, and stirred at −20° C. overnight. Theresulting faint yellow solid was collected by vacuum filtration, washedwith cold heptane (500 mL), and dried under vacuum overnight at roomtemperature to give the title compound (549 g, 71%). ¹H NMR (CDCl₃, 400MHz): δ 6.35 (s, 2H), 4.85 (d, 2H), 2.8 (m, 2H), 0.95 (d, 6H).

(1R,2R,4S,5S,6S,8R)-6,8-dimethyl-3,9-dioxatricyclo[3.3.1.02,4]nonan-7-one

To a stirred solution of(1R,2S,4R,5S)-2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6-en-3-one (1.06 kg)in 1,2-dichloroethane (10 L) at room temperature was addedm-chloroperbenzoic acid (1.80 kg) in one portion. The resultingsuspension was stirred under reflux (at 70-75° C.) for 5 h. Morem-chloroperbenzoic acid (180 g) was added and stirring was continued foradditional 3 h. The mixture was cooled to 0° C. and stirred at 0° C.overnight. The resulting precipitate was filtered and washed withmethylene chloride (4 L). The filtrate was sequentially washed with 10 Msodium carbonate in water (7 L) and water (4 L). The organic layer wasconcentrated in vacuo and chased twice with n-heptane (2 L). Theresulting pale yellow solid was dissolved in MTBE (2.5 L) by heating to55° C., treated with n-heptane (0.8 L), and stood at −20° C. for 3 days.The precipitate was collected by vacuum filtration and washed with a 3:2mixture of MTBE and n-heptane (750 mL) to give the title compound (1050g, 90%) as a white solid. ¹H NMR (CDCl₃, 400 MHz): δ 4.40 (t, 2H), 3.55(t, 2H), 2.80 (m, 2H), 1.05 (d, 6H).

Synthesis of rac-6,7-dimethylhexahydro-2,5-methanofuro[3,2-b]furan-3-ol

To a cold (−15° C.) suspension of sodium borohydride (337 g) in methanol(4 L) in a 22 L reactor under nitrogen was carefully charged a solutionof(1R,2R,4S,5S,6S,8R)-6,8-dimethyl-3,9-dioxatricyclo[3.3.1.02,4]nonan-7-one(1 kg) in a mixture of methanol (2 L) and methylene chloride (4 L) over1.5 h maintaining the internal temperature below 0° C. The resultingmixture was stirred at −5-0° C. for 2 h. After quenching the reactionwith water (160 mL), the mixture was concentrated under vacuum andchased with methylene chloride (2 L). The resulting solid was dissolvedin methylene chloride (8 L) and washed with water (4 L). The aqueouslayer was back-extracted with methylene chloride (4 L). The organiclayers were combined, dried over anhydrous sodium sulfate and stood at0° C. overnight. The sodium sulfate was removed by vacuum filtration andrinsed with methylene chloride (1 L).

The filtrate was treated with 5.5 M HCl in isopropyl alcohol (3 L) at 5°C. and stirred at 20-30° C. for 1 h. The reaction mixture wasconcentrated under vacuum at 30° C. and chased twice with toluene (2 L)to give the title compound (975 g, 96%) as a pale yellow solid. ¹H NMR(C₆D₆, 400 MHz): 4.30 (t, 1H), 4.10 (t, 1H), 4.00 (t, 1H), 3.75 (t, 1H),3.15 (t, 1H), 2.45 (s, 1H), 1.85 (m, 1H), 1.45 (m, 1H), 0.60 (d, 3H),0.55 (d, 3H).

Synthesis of the Corresponding Phthalate of the Racemic Alcohol

rac-6,7-Dimethylhexahydro-2,5-methanofuro[3,2-b]furan-3-ol (970 g) wasdissolved in a mixture of triethylamine (1.99 L) and toluene (2.1 L),treated with phthalic anhydride (925 g), and stirred at 70° C. for 2 h.The mixture was cooled to 10° C. and treated with 3 M hydrogen chloridein water (7 L) maintaining the temperature below 30° C. White solidsbegan falling out of solution. The mixture was stirred at rt for anadditional 20 min. The white solid product was then collected by vacuumfiltration, washed with water (2 L), and dried under vacuum. The crudeproduct was chased with toluene (4 L) and then heated in toluene (5.6 L)to 70° C. to obtain a clear solution. The solution was allowed to coolto 65° C. where solids began falling out of solution, and slowly cooledto rt overnight. The white solid product was collected by vacuumfiltration, washed with toluene (1 L), and dried under vacuum. Theproduct was recrystallized again in toluene (5.6 L) by heating to 75°,cooling to rt at a rate of 10° C. per hour, and stirring at rtovernight. Solids began falling out of solution at 65° C. The resultingprecipitate was collected by vacuum filtration, washed with toluene (1L), and dried under vacuum at 40° C. to give the title compound (1.65kg, 91%) as a white solid. ¹H NMR analysis showed that there was 4% ofthe suspected equatorial by-product and approximately 4% oftriethylamine salt present. ¹H NMR (CDCl₃, 400 MHz): 7.80 (d, 1H), 7.65(d, 1H), 7.55 (m, 2H), 5.50 (s, 1H), 4.80 (t, 1H), 4.50 (t, 1H), 4.35(t, 1H), 3.75 (t, 1H), 3.10 (m, 1H), 2.00 (m, 1H), 1.05 (d, 3H), 0.85(d, 3H).

Resolution of the Phthalate with α-methylbenzylamine:

A phthalate ofrac-6,7-dimethylhexahydro-2,5-methanofuro[3,2-b]furan-3-ol (800 g) wasdissolved in acetone (12 L) with slight heating to 50° C. The resultingclear solution was treated with (S)-methylbenzylamine (324 mL) andstirred at 50° C. for 10 min. The mixture was stirred at 45° C. for 1 h,at 40° C. for 1 h, and at 35° C. for 1 h before cooling to 18-22° C.over 2 h. The mixture was then allowed to stir at 18-22° C. for 17 h.The solid precipitate was collected by vacuum filtration, washed withacetone (1 L), and dried under vacuum at 30° C. to give(S)-1-phenylethanaminium 2-((((2R,3R,3aR,5S,6R,6aS,7S)-6,7-dimethylhexahydro-2,5-methanofuro[3,2-b]furan-3-yl)oxy)carbonyl)benzoate (372 g,36.6%, dr=98.4:1.6 by chiral HPLC) as a white solid. ¹H NMR (CDCl₃, 400MHz): δ 8.1 (bs, 3H), 7.60 (d, 1H), 7.55 (d, 1H), 7.30-7.40 (m, 4H),7.20 (m, 3H), 5.30 (s, 1H), 4.60 (t, 1H), 4.30 (t, 1H), 4.25 (t, 1H),3.95 (t, 1H), 3.65 (t, 1H), 2.10 (m, 1H), 1.85 (m, 1H), 1.70 (d, 3H),0.95 (d, 3H), 0.75 (d, 3H).

The filtrate was concentrated under vacuum and then dissolved in MTBE (4L). The solution was then washed with 1.0 M aqueous HCl (3 L) and theaqueous layer was back extracted with MTBE (2 L). The organic layerswere combined, washed with water (2 L), and concentrated under vacuum at30° C. to give a red-brown foam. The foam was chase with MTBE (2 L) andthen with acetone (2 L). The brown foam (520 g) was dissolved in acetone(7.8 L) at 50° C. and treated with (R)-α-methylbenzylamine (210 mL). Themixture was stirred at 50° C. for 10 min, at 45° C. for 1 h, at 40° C.for 1 h, and at 35 for 1 h before cooling to 18-22° C. over 2 h. Themixture was then allowed to stir at 18-22° C. over 17 h. The precipitatewas collected by vacuum filtration, washed with acetone (0.5 L), anddried under vacuum at 35° C. to give (R)-1-phenylethanaminium2-((((2S,3S3aS,5R,6S,6aR,7R)-6,7-dimethylhexahydro-2,5-methanofuro[3,2-b]furan-3-yl)oxy)carbonyl)benzoate(402 g, 40%, dr=96.7:3.3 by chiral HPLC) as a white solid. ¹H NMR(CDCl₃, 400 MHz): δ 8.1 (bs, 3H), 7.60 (d, 1H), 7.55 (d, 1H), 7.30-7.40(m, 4H), 7.20 (m, 3H), 5.30 (s, 1H), 4.60 (t, 1H), 4.30 (t, 1H), 4.25(t, 1H), 3.95 (t, 1H), 3.65 (t, 1H), 2.10 (m, 1H), 1.85 (m, 1H), 1.70(d, 3H), 0.95 (d, 3H), 0.75 (d, 3H).

(2R,3R,3aS,5R,6R,6aS,7S)-6,7-dimethylhexahydro-2,5-methanoforo[3,2-b]furan-3-ol

(S)-1-phenylethanaminium2-((((2R,3R,3aR,5S,6R,6aS,7S)-6,7-dimethylhexahydro-2,5-methanofuro[3,2-b]furan-3-yl)oxy)carbonyl)benzoate(362 g) was dissolved in 1.0 M aqueous HCl (1.7 L) and MTBE (2 L). Theorganic layer was separated and the aqueous layer was extracted withMTBE (1 L). The organic layers were combined, washed with 1.0 M aqueousHCl (0.4 L), and treated with a solution of sodium hydroxide (99 g) inwater (1 L). After stirring at rt for 1 h, the organic layer wasseparated and the aqueous layer was extracted with MTBE (1 L×2) andethyl acetate (0.5 L). The combined organic layers were concentratedunder vacuum to give the title compound (127 g, 91%) as a white solid.¹H NMR (CDCl₃, 400 MHz): δ 4.50 (t, 1H), 4.40 (t, 1H), 4.20 (t, 1H),4.00 (t, 1H), 3.70 (s, 1H), 2.30 (m, 1H), 2.20 (m, 1H), 2.00 (m, 1H),1.00 (d, 3H), 0.90 (d, 3H).

(2S,3S,3aR,5S,6S,6aR,7R)-6,7-dimethylhexahydro-2,5-methanofuro[3,2-b]furan-3-ol

(R)-t-phenylethanaminium2-((((2S,3S,3aS,5R,6S,6aR,7R)-6,7-dimethylhexahydro-2,5-methanofuro[3,2-b]furan-3-yl)oxy)carbonyl)benzoate(397 g) was dissolved in a mixture of 1.0 M aqueous HCl (1.9 L) and MTBE(2 L). The organic layer was separated and the aqueous layer wasextracted with MTBE (1 L). The organic layers were combined, washed with1.0 M aqueous HCl (0.5 L), and then treated with a solution of sodiumhydroxide (108 g) in water (l L). After stirring at rt for 1 h, theorganic layer was separated and the aqueous layer was extracted withMTBE (1 L×2) and ethyl acetate (0.5 L). The combined organic layers wereconcentrated under vacuum to give the title compound (135.8 g, 88%) as awhite solid. ¹H NMR (CDCl₃, 400 MHz): δ 4.40 (t, 1H), 4.30 (t, 1H), 4.20(t, 1H), 4.00 (t, 1H), 3.70 (s, 1H), 2.30 (m, 2H), 2.00 (m, 1H), 1.00(d, 3H), 0.90 (d, 3H).

B. Stereochemistry Determination for Compounds of Formula 1.

The stereochemistry of compounds of Formula 1 was determined usingMosher ester reacations as described below.

Mosher ester of(2R,3R,3aS,5R,6R,6aS,7S)-6,7-dimethylhexahydro-2,5-methanofuro[3,2-b]furan-3-ol

(S)-1-1-phenylethanaminium2-((((2R,3R,3aR,5S,6R,6aS,7S)-6,7-dimethylhexahydro-2,5-methanofuro[3,2-b]furan-3-yl)oxy)carbonyl)benzoate(105 mg, 0.24 mmol) was suspended in MTBE (6 mL) and washed twice with 1N aqueous HCl (1 mL). The organic layer was treated with 3 N NaOH (1 mL)and stirred at rt for 1 h. The organic layer was separated, dried overMgSO₄ and concentrated in vacuo to give a crude alcohol.

Ca. 5 mg of the crude alcohol was dissolved in CH₂Cl₂ (0.3 mL) andtreated with triethylamine (30 uL),(S)-methoxy-trifluoromethylphenylacetyl chloride (18 mg) and a catalyticamount of DMAP. After stirring at rt for 30 min, the mixture was dilutedwith water (5 mL) and MTBE (5 mL). The organic layer was separated,filtered through silica gel pad, and concentrated in vacuo to give acrude Mosher ester, which was analyzed by NMR. ¹H NMR (CDCl₃, 400 MHz):δ 7.58 (m, 2H, Ph), 7.42 (m, 3H, Ph), 5.37 (s, 1H, C3-H), 4.72 (m, 1H,C3a-H), 4.42 (m, 1H, C6a-H), 4.30 (m, 1H, C2-H), 3.80 (s, lit, C5-H),3.55 (s, 3H, OMe), 2.35 (q, 1H, C6-H), 2.07 (m, 1H, C7-H), 1.12 (d, 3H,Me), 0.89 (d, 3H, Me).

Mosher Ester of a Racemic Alcohol:

The phthalate of racemic alcohol (77 mg) prepared by above procedure wasdissolved in MTBE (6 mL) and treated with 3 N NaOH (1 mL). Afterstirring at rt for 1 h, the organic layer was separated, dried overMgSO4 and concentrated in vacuo.

Ca. 5 mg of the crude alcohol was dissolved in CH₂Cl₂ (0.3 mL) andtreated with triethylamine (30 uL),(S)-methoxy-trifluoromethylphenylacetyl chloride (18 mg) and a catalyticamount of DMAP. After stirring at rt for 30 min, the mixture was dilutedwith water (5 mL) and MTBE (5 mL). The organic layer was separated,filtered through silica gel pad, and concentrated in vacuo to give acrude Mosher ester, which was analyzed by NMR. Peaks corresponding tothe compound A and B was assigned based on literature (Rieser, M. J. etal., J. Am. Chem. Soc. 1992, 114, 10203). ¹H NMR (CDCl₃, 400 MHz): δ7.58 (m, 4H, Ph), 7.42 (m, 6H, Ph), 5.37 (s, 2H, C3-H for A and B), 4.72(m, 1H, C3a-H for A), 4.62 (m, 1H, C3a-H for B), 4.42 (m, 2H, C5a-H forA and B), 4.38 (m, 1H, C2-H for B), 4.30 (m, 1H, C2-H for A), 3.80 (s,2H, C5-H for A and B), 3.60 (s, 3H, OMe for B), 3.55 (s, 3H, OMe for A),2.35 (m, 2H, C6-H for A and B), 2.07 (m, 2H, C.7-H for A and B), 1.12(d, 3H), 1.10 (d, 3H), 0.89 (2d, 6H).

C. Oxidation of Alcohols of Formulas 1a and 1b to Lactones of FormulasIa and Ib, Respectively.

Compounds of Formulas Ia and Ib were prepared as shown in Scheme 2 anddescribed below.

(2S,3aS,5R,6S,6aR,7R)-6,7-dimethyltetrahydro-2,5-methanofuro[3,2-b]furan-3(2H)-one

Sulfur trioxide-pyridine complex (118 g, 741 mmol) was dissolved in DMSO(400 mL) and stirred at ambient temperature for 20 min. After cooling to0° C., the mixture was treated with a mixture of(2S,3S,3aR,5S,6S,6aR,7R)-6,7-dimethylhexahydro-2,5-methanofuro[3,2-b]furan-3-ol(42.2 g, 248 mmol) and triethylamine (207 mL, 1.49 mol) in methylenechloride (400 mL) over 1 h maintaining the internal temperature below10° C. After stirring at ambient temperature for 4 h, the reaction wasquenched with water (400 mL). The organic layer was separated and theaqueous layer was extracted with MTBE (500 mL). The organic layers werecombined, washed twice with water (200 mL) and then with brine (150 mL),and concentrated in vacuo.

The residue was dissolved in MTBE (50 mL) and treated with n-heptane(200 mL). The resulting turbid solution was stirred at ambienttemperature for 18 h. The precipitate was filtered, washed withn-heptane (20 mL), and dried under nitrogen purge to give the titlecompound (1^(st) crop, 5.4 g, 13%). The filtrate was concentrated invacuo and dissolved in a mixture of MTBE (2 mL) and n-heptane (55 mL)with heating. The resulting clear solution was stirred at ambienttemperature for 1 h and at 0° C. for 3 h. The precipitate was filteredand washed with n-heptane to give the 2^(nd) crop (13.8 g, 33%). ¹H NMR(CDCl₃, 400 MHz): δ 4.68 (m, 1H), 4.29 (m, 1H), 3.96 (s, 1H), 3.90 (m,1H), 2.48 (q, 1H), 2.36 (m, 1H), 1.10 (d, 3H), 0.93 d, 3H).

(2S,4aR,6R,7S,7aR,8R)-7,8-dimethyltetrahydro-2,6-methanofuro[2,3-b][1,4]dioxin-3(2H)-one

(2S,3aS,5R,6S,6aR,7R)-6,7-dimethyltetrahydro-2,5-methanofuro[3,2-b]furan-3(2H)-one(7.07 g, 45.8 mmol) was dissolved in methylene chloride (120 mL) andtreated with m-chloroperbenzoic acid (14.1 g, 81.7 mmol). After stirringat rt for 18 h, the mixture was diluted with MTBE (150 mL) and washedwith 1 N aqueous NaOH solution (50 mL) and brine (30 mL). The organiclayer was separated, dried over MgSO₄ and concentrated in vacuo. Theresidue was further purified by crystallization with MTBE and n-heptaneto give the title compound (total 5.9 g, 62.7%). ¹H NMR (CDCl₃, 400MHz): δ 5.95 (t, 1H), 4.35 (t, 1H), 4.20 (t, 1H), 3.95 (t, 1H), 2.40 (m,1H), 2.10 (m, 1H), 1.00 (d, 3H), 0.95 (d, 3H).

(2S,4aR,6R,7S,7aR,8R)-7,8-dimethyltetrahydro-2,6-methanofuro[2,3-b][1,4]dioxin-3(2H)-one

(2S,3S,3aR,5S,6S,6aR,7R)-6,7-dimethylhexahydro-2,5-methanofuro[3,2-b]furan-3-ol(20 g) was dissolved in a mixture of methylene chloride (300 mL) andsaturated aqueous NaHCO₃ (230 mL). After cooling to 0° C., the mixturewas treated with 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (370mg) and m-chloroperbenzoic acid (105 g). The mixture was stirred at 0°C. for 10 min and at rt for 16 h. After dilution with MTBE (400 mL), theorganic layer was separated, and sequentially washed with a solution ofsodium bisulfite (37 g) in water (100 mL), saturated aqueous NaHCO₃ (150mL×3), and water (100 mL). The organic layer was concentrated undervacuum at 30° C. and chased with MTBE (100 mL) to furnish a yellow-whitesolid. The crude product was recrystallized from isopropyl alcohol (65mL) by heating to 55° C., slowly cooling to rt over 4 h, and stirring at0° C. for 1 h. The precipitate was collected by vacuum filtration,washed with isopropyl alcohol (15 mL), and dried under vacuum to givethe title compound (16.5 g, 76%) as a white solid. [α]_(D) ²⁰=+269.7° (c0.51, MeOH); ¹H NMR (CDCl₃, 400 MHz): δ 5.95 (t, 1H), 4.35 (t, 1H), 4.20(t, 1H), 3.95 (t, 1H), 2.40 (m, 1H), 2.10 (m, 1H), 1.00 (d, 3H), 0.95(d, 3H).

(2R,4aS,6S,7R,7aS,8S)-7,8-dimethyltetrahydro-2,6-methanofuro[2,3-b][1,4]dioxin-3(2H)-one

(2R,3R,3aS,5R,6R,6aS,7S)-6,7-dimethylhexahydro-2,5-methanofuro[3,2-b]furan-3-ol(100 g) was dissolved in a mixture of methylene chloride (1.5 L) andsaturated aqueous NaHCO₃ (1.15 L). After cooling to 10° C., the mixturewas treated with 2,2,6,6-tetramethyl-1-piperidinyloxy, free radical (1.8g) and m-chloroperbenzoic acid (530 g). The mixture was stirred at 10°C. for 30 min and at rt overnight. After dilution with MTBE (2 L), theorganic layer was separated, and sequentially washed with a solution ofsodium bisulfite (167 g) in water (1 L), saturated aqueous NaHCO₃ (1L×3), and water (500 mL). The organic solution was then concentratedunder vacuum and chased with toluene (1 L). The resulting solid wassuspended in toluene (350 mL), heated to 45° C. and then allowed to coolto rt overnight. The white solid precipitate (mCPBA residue) wascollected by vacuum filtration and washed with toluene (50 mL). Thefiltrate was concentrated under vacuum and recrystallized from isopropylalcohol (300 mL) by dissolving at 55° C., slowly cooling to 22° C. over1.5 h, and stirring at 0-5° C. for 1 h. The precipitate was collected byvacuum filtration, washed with isopropyl alcohol (75 mL), and driedunder vacuum at 35° C. to give the title compound (85.5 g, 79%) as awhite solid. [α]_(D)=−248.6° (c 0.52, MeOH); ¹H NMR (CDCl₃, 400 MHz): δ5.95 (t, 1H), 4.40 (t, 1H), 4.20 (t, 1H), 4.00 (t, 1H), 2.40 (m, 1H),2.20 (m, 1H), 1.05 (d, 3H), 1.00 (d, 3H).

D. Elaboration of Lactone of Formula a to Protected Tetrad 3

A compound of Formula Ia was elaborated as shown in Scheme 3 anddescribed below.

Methyl 6(1,3-dithiolan-2-yl)-4-hydroxy-3,5-dimethyltetrahydro-2H-pyran-2-carboxylate

7,8-dimethyltetrahydro-2,6-methanofuro[2,3-b][1,4]dioxin-3(2H)-one (20mg, 0.11 mmol) was dissolved in 4 M hydrogen chloride in 1,4-dioxane(0.5 mL, 18 equiv) and treated with methanol (0.044 mL) and1,2-ethanedithiol (0.020 mL, 2 equiv). After stirring at rt for 3 days,the reaction was quenched with sat. NaHCO3. The mixture was extractedwith MTBE. The organic layer was washed with brine and concentrated invacuo. The crude product was purified by column chromatography (ethylacetate/n-heptane=1/10 to 1/3) to give the title compound (3 mg, 9%) asa white solid. ¹H NMR (CDCl₃, 400 MHz): δ 4.70 (d, 1H), 4.16 (dd, 1H),4.04 (t, 1H), 3.82 (s, 3H), 3.33 (dd, 1H), 3.20-3.28 (m, 4H), 2.26 (m,2H), 1.06 (d, 3H), 0.96 (d, 3H).

(2S,3R,4R,5S,6S)-methyl4-hydroxy-6-((E)-3-methoxy-3-oxoprop-1-en-1-yl)-3,5-dimethyltetrahydro-2H-pyran-2-carboxylate

(2S,4aR,6R,7S,7aR,8R)-7,8-dimethyltetrahydro-2,6-methanofuro[2,3-b][1,4]dioxin-3(2H)-one(114 mg, 0.62 mmol) was dissolved in a mixture of methanol (1 mL) andtetrahydrofuran (0.2 mL), cooled to 0° C. and treated with trimethylphosphonoacetate (0.15 mL, 1.5 equiv). Sodium methoxide (25% inmethanol, 0.169 mL, 3.0 equiv) was added over 5 min and the resultingmixture was stirred at 0° C. for 40 min. The mixture was diluted with2-methoxy-2-methylpropane (10 mL), and washed twice with water (5 mL)and then with sat. NH4Cl (5 mL) and brine (5 mL). The organic layer wasconcentrated in vacuo to give the title compound (117 mg, 70%) as awhite solid. ¹H NMR (CDCl₃, 400 MHz): δ 6.90 (dd, 1H), 6.38 (dd, 1H),4.19 (m, 2H), 4.12 (m, 1H), 3.82 (s, 31H), 3.78 (s, 3H), 2.40 (m, 1H),2.12 (m, 1H), 1.76 (bd, 1H), 0.98 (d, 3H), 0.98 (d, 3H).

(2S,3R,4R,5S,6R)-methyl 4-hydroxy-3,5-dimethyl-6-((E)-2-(phenysulfonyl)vinyl)tetrahydro-2H-pyran-2-carboxylate

A mixture of(2S,4aR,6R,7S,7aR,8R)-7,8-dimethyltetrahydro-2,6-methanofuro[2,3-b][1,4]dioxin-3(2H)-one(5.25 g, 28.5 mmol) and dimethyl ((phenylsulfonyl)methyl)phosphonate(8.75 g, 30.0 mmol, 1.05 equiv) was dissolved in a mixture of methanol(54.6 mL) and tetrahydrofuran (27.3 mL). After cooling to 0° C., themixture was treated with sodium methoxide (25% solution in methanol,5.97 mL, 2.3 equiv) and stirred at 0° C. for 1 h.

The mixture was diluted with 2-methoxy-2-methylpropane (100 mL) andsequentially washed with water (50 mL) and saturated aqueous NaHCO3 (50mL). The aqueous layers were combined and back-extracted with2-methoxy-2-methylpropane (50 mL). The organic layers were combined,dried over MgSO4 and concentrated in vacuo to give the title compound(10.3 g, 97%). ¹H NMR (CDCl₃, 400 MHz): δ 7.92 (m, 2H), 7.62 (m, 1H),7.58 (m, 2H), 6.90 (dd, 1H), 6.82 (dd, 1H), 4.22 (m, 1H), 4.19 (m, 1H),4.13 (d, 1H), 4.10 (t, 1H), 3.78 (s, 3H), 2.36 (m, 1H), 2.15 (m, 1H),0.91 (d, 3H), 0.88 (d, 3H).

(2S,3R,4R,5S,6S)-methyl4-hydroxy-3,5-dimethyl-6-(2-(phenylsulfonyl)ethyl)tetrahydro-2H-pyran-2-carboxylate

(2S,3R,4R,5S,6R)-methyl 4-hydroxy-3,5-dimethyl-6-((E)-2-(phenylsulfonyl)vinyl)tetrahydro-2H-pyran-2-carboxylate (9.1 g, 25.7 mmol) was dissolvedin a mixture of ethyl acetate (100 mL) and methanol (20 mL), and treatedwith 10% Pd/C (50% wet, Degussa type E101 NE/W, 550 mg). The mixture wasstirred under hydrogen atmosphere (balloon) for 15 h. The catalyst wasfiltered off using celite pad and washed with ethyl acetate. Thefiltrate was concentrated in vacuo to give the title compound (11.23 g),which was used for the next step without further purification. ¹H NMR(CDCl₃, 400 MHz): δ 7.96 (m, 2H), 7.65 (m, 1H), 7.61 (m, 2H), 4.20 (m,1H), 4.00 (m, 1H), 3.78 (s, 3H), 3.52 (m, 1H), 3.38 (m, 1H), 3.22 (m,1H), 2.22 (m, 1H), 2.18 (m, 1H), 1.92 (m, 2H), 0.94 (d, 3H), 0.90 (d,3H).

(2S,3S,4R,5R,6S)-methyl3,5-dimethyl-6-(2-(phenylsulfonyl)ethyl)-4-((triethylsilyl)oxy)tetrahydro-2H-pyran-2-carboxylate

A solution of (2S,3R,4R,5S,6S)-methyl4-hydroxy-3,5-dimethyl-6-(2-(phenylsulfonyl)ethyl)tetrahydro-2H-pyran-2-carboxylate(9.15 g, 25.7 mmol) in methylene chloride (100 mL) was cooled to 0° C.and treated with imidazole (3.5 g, 2.0 equiv) and chlorotriethylsilane(4.74 mL, 1.1 equiv). The mixture was stirred at rt for 21 h. Theresulting mixture was diluted with 2-methoxy-2-methylpropane (150 mL),sequentially washed with water (70 mL) and brine (30 mL), andconcentrated in vacuo. The resulting crude product was purified bycolumn chromatography (ethyl acetate/n-heptane=1/10 to 1/3) to give thetitle compound (10.75 g, 94% for two steps). ¹H NMR (CDCl₃, 400 MHz): δ7.96 (m, 2H), 7.65 (m, 1H), 7.61 (m, 2H), 3.98 (m, 1H), 3.90 (t, 1H),3.78 (s, 3H), 3.49 (m, 1H), 3.38 (m, 1H), 3.21 (m, 1H), 2.16 (m, 2H),1.92 (m, 1H), 1.78 (m, 1H), 1.00 (t, 9H), 0.92 (d, 3H), 0.88 (d, 3H),0.62 (q, 6H).

((2S,3S,4R,5R,6S)-3,5-dimethyl-6-(2-(phenylsulfonyl)ethyl)-4-((triethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methanol

(2S,3S,4R,5R,6S)-methyl3,5-dimethyl-6-(2-(phenylsulfonyl)ethyl)-4-((triethylsilyl)oxy)tetrahydro-2H-pyran-2-carboxylate(1.0 g, 2.1 mmol) was dissolved in tetrahydrofuran (13 mL) and cooled to0° C. 2 M Lithium tetrahydroborate in tetrahydrofuran (2.46 mL, 2.3equiv) was added and the resulting mixture was stirred at rt for 22 h.After cooing to 0° C., the mixture was diluted with2-methoxy-2-methylpropane (20 mL) and treated with 20 wt % citric acid(3.87 mL) maintaining the internal temperature below 10° C. The mixturewas vigorously stirred for 10 min. The organic layer was separated andthe aqueous layer was extracted with 2-methoxy-2-methylpropane (20 mL).The organic layers were combined, washed twice with sat. NaHCO3 and thenconcentrated under vacuum to give the title compound (0.90 g, 95%) as aclear oil. ¹H NMR (CDCl₃, 400 MHz): δ 7.95 (m, 2H), 7.65 (m, 1H), 7.60(m, 2H), 3.83 (m, 1H), 3.72 (m, 1H), 3.40-3.52 (m, 3H), 3.32 (m, 1H),3.19 (m, 1H), 2.10 (m, 1H), 1.70-1.90 (m, 3H), 0.80-1.00 (m, 15H), 0.60(q, 6H).

Triethyl(((2S,3S,4R,5R,6S)-2-(iodomethyl)-3,5-dimethyl-6-(2-(phenylsulfonyl)ethyl)tetrahydro-2H-pyran-4-yl)oxy)silane

((2S,3S,4R,5R,6S)-3,5-dimethyl-6-(2-(phenylsulfonyl)ethyl)-4-((triethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methanol(0.18 g, 0.40 mmol) was dissolved in tetrahydrofuran (3 mL) and treatedwith triphenylphosphine (0.21 g, 2.0 equiv) and imidazole (82 mg, 3.0equiv). After cooling to 0° C., the mixture was treated with iodine(0.15 g, 2.0 equiv) and stirred at rt for 5 h. More triphenylphosphine(0.21 g, 2.0 equiv), imidazole (82 mg, 3.0 equiv) and iodine (0.15 g,2.0 equiv) were added, and stirring was continued at rt for 15 h and at40° C. for 5 h. After cooling to rt, the reaction was quenched with 10%aqueous sodium thiosulfate solution (5 mL) and extracted with MTBE.After concentration, the crude product was purified by columnchromatography (MTBE/n-heptane=1/10 to 1/3) to give the title compound(172 mg, 77%). ¹H NMR (CDCl₃, 400 MHz): δ 7.95 (m, 2H), 7.65 (m, 1H),7.60 (m, 2H), 3.80 (m, 1H), 3.42-3.58 (m, 2H), 3.40 (m, 1H), 3.24 (m,1H), 3.22 (m, 1H), 2.10 (m, 1H), 1.98 (m, 1H), 1.82 (m, 1H), 1.68 (m,1H), 0.98 (t, 9H), 0.86 (d, 3H), 0.82 (d, 3H), 0.60 (q, 6H).

(3S,4R,5S,6S)-4,6-dimethyl-1-(phenylsulfonyl)-5-((triethylsilyl)oxy)oct-7-en-3-ol

To a cooled (0° C.) mixture of zinc (0.101 g, 5 equiv) and acetic acid(0.035 mL, 2.0 equiv) in water (0.3 mL) was added a solution oftriethyl(((2S,3S,4R,5R,6S)-2-(iodomethyl)-3,5-dimethyl-6-(2-(phenylsulfonyl)ethyl)tetrahydro-2H-pyran-4-yl)oxy)silane(0.17 g, 1.3 mmol) in tetrahydrofuran (1 mL). After stirring at 0° C.for 2 h, the mixture was diluted with 2-methoxy-2-methylpropane (20 mL).The mixture was sequentially washed with water (5 mL) and saturatedaqueous NaHCO3 (5 mL), concentrated in vacuo and purified by columnchromatography (MTBE/n-heptane=1/10 to 1/2) to give the title compound(104 mg, 79%). ¹H NMR (CDCl₃, 400 MHz): δ 7.93 (m, 2H), 7.63 (m, 1H),7.58 (m, 2H), 5.74 (m, 1H), 5.02 (m, 2H), 4.01 (m, 1H), 3.55 (dd, 1H),3.50 (s, 1H), 3.34 (m, 1H), 3.08 (m, 1H), 2.39 (m, 1H), 1.88 (m, 1H),1.60-1.76 (m, 2H), 0.86-0.96 (m, 15H), 0.60 (m, 6H).

(5S,6R,7S)-5-((S)-but-3-en-2-yl)-3,3,9,9-tetraethyl-6-methyl-7-(2-(phenylsulfonyl)ethyl)-4,8-dioxa-3,9-disilaundecane

A solution of(3S,4R,5S,6S)-4,6-dimethyl-1-(phenylsulfonyl)-5-((triethylsilyl)oxy)oct-7-en-3-ol(0.36 g, 0.84 mmol) in methylene chloride (4.5 mL) was cooled to 0° C.,treated with imidazole (0.172 g, 3.0 equiv) and chlorotriethylsilane(0.212 mL, 0.15 equiv), and stirred at rt for 7 h. More imidazole (30mg, 0.52 equiv) and chlorotriethylsilane (20 □L, 0.14 equiv) were addedand stirring was continued at rt for additional 16 h. After quenchingthe reaction with water (10 mL), the mixture was extracted with2-methoxy-2-methylpropane (10 mL). The separated organic layer waswashed with brine and concentrated in vacuo. The crude product waspurified by column chromatography (MTBE/n-heptane=l/20 to 1/5) to givethe title compound (342 mg, 75%). ¹H NMR (CDCl₃, 400 MHz): δ 7.95 (m,2H), 7.66 (m, 1H), 7.61 (m, 2H), 5.87 (m, 1H), 4.95 (m, 2H), 3.82 (m,1H), 3.49 (dd, 1H), 3.20 (m, 1H), 3.06 (m, 1H), 2.26 (m, 1H), 1.8-2.0(m, 2H), 1.50 (m, 1H), 0.86-1.00 (min, 21H), 0.82 (d, 3H), 0.50-0.66 (m,12H).

E. Synthesis of Protected Pentads 4 and 5

Protected pentads of Formulas 4 and 5 were synthesized from a compoundof Formula Ia as shown in Scheme 4 and described below.

(2S,3S,4R,5R,6R)-methyl3,5-dimethyl-6-((E)-2-(phenylsulfonyl)vinyl)-4-((triethylsilyl)oxy)tetrahydro-2H-pyran-2-carboxylate

A solution of (2S,3R,4R,5S,6R)-methyl4-hydroxy-3,5-dimethyl-6-((E)-2-(phenylsulfonyl)vinyl)tetrahydro-2H-pyran-2-carboxylate(1.0 g, 2.8 mmol) in methylene chloride was cooled to 0° C. and treatedwith imidazole (0.406 g, 2.1 equiv) and chlorotriethylsilane (0.521 mL,1.1 equiv). After stirring at rt for 4 h, the mixture was diluted with2-methoxy-2-methylpropane (20 mL) and washed with water (10 mL) andbrine (10 mL). After concentration, the crude product was purified bycolumn chromatography (MTBE/n-heptane=1/10 to 1/2) to give the titlecompound (1.11 g, 88%). ¹H NMR (CDCl₃, 400 MHz): δ 7.92 (m, 2H), 7.65(m, 1H), 7.58 (m, 2H), 6.90 (dd, 1H), 6.80 (dd, 1H), 4.20 (m, 1H), 4.12(m, 1H), 4.02 (t, 1H), 3.78 (s, 3H), 2.22 (m, 1H), 2.02 (m, 1H), 1.01(t, 9H), 0.89 (d, 3H), 0.87 (d, 3H), 0.64 (q, 6H).

((2S,3S,4R,5R,6R)-3,5-dimethyl-6-((E)-2-(phenylsulfonyl)vinyl)-4-((triethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methanol

To a cooled (−70° C.) solution of (2S3S,4R,5R,6R)-methyl3,5-dimethyl-6-((E)-2-(phenylsulfonyl)vinyl)-4-((triethylsilyl)oxy)tetrahydro-2H-pyran-2-carboxylate(7.91 g, 16.9 mmol) in methylene chloride (80 mL) was added 1 Mdiisobutylaluminum hydride in toluene (37.1 mL, 2.2 equiv). Afterstirring at −65° C. for 1 h, additional 1 M diisobutylaluminum hydridein toluene (5.1 mL, 0.3 equiv) was added and stirring was continued at−65° C. for additional 0.5 h. After quenching the reaction with methanol(3.3 mL), the mixture was stirred at −65° C. for 5 min, poured intosaturated aqueous sodium potassium tartrate (180 mL), and vigorouslystirred at rt for 1 h. Then, the mixture was extracted twice with2-methoxy-2-methylpropane (100 mL). The organic layers were combined andconcentrated in vacuo.

The residue was dissolved in methanol (66 mL), cooled to 0° C., andtreated with sodium tetrahydroborate (0.19 g, 0.3 equiv). After stirringfor 1 h at 0° C., the reaction was quenched with 0.1 M hydrogen chloridein water (66 mL) and the mixture was extracted twice with2-methoxy-2-methylpropane (60 mL). The organic layers were combined,sequentially washed with sat. NaHCO3 (30 mL) and brine (30 mL), andconcentrated in vacuo. The crude product was purified by columnchromatography (ethyl acetate/n-heptane=1/10 to 1/2) to give the titlecompound (4.76 g, 95%). ¹H NMR (CDCl₃, 400 MHz): δ 7.93 (m, 2H), 7.66(m, 1H), 7.57 (m, 2H), 6.90 (dd, 1H), 6.64 (dd, 1H), 4.22 (m, 1H), 3.95(t, 1H), 3.78 (m, 1H), 3.58 (m, 1H), 3.52 (m, 1H), 2.00 (m, 1H), 1.82(m, 1H), 1.79 (m, 1H), 0.98 (t, 9H), 0.86 (d, 3H), 0.82 (d, 3H), 0.62(q, 6H).

triethyl((2S,3S,4R,5R,6R)-2-(iodomethyl)-3,5-dimethyl-6-((E)-2-(phenylsulfonyl)vinyl)tetrahydro-2H-pyran-4-yl)oxy)silane

((2S,3S,4R,5R,6R)-3,5-dimethyl-6-((E)-2-(phenylsulfonyl)vinyl)-4-((triethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methanol(4.54 g, 10.3 mmol) was dissolved in tetrahydrofuran (85 mL) and treatedwith triphenylphosphine (9.47 g, 3.5 equiv) and imidazole (4.21 g, 6equiv). After addition of iodine (7.85 g, 3 equiv), the mixture wasstirred at rt for 1 h and at 40° C. for 22 h. The mixture was cooled tort and diluted with n-heptane (50 mL). The resulting precipitate wasfiltered and washed with 2-methoxy-2-methylpropane (100 mL). Thefiltrate was sequentially washed with 10% aqueous sodium thiosulfatesolution (80 mL) and brine (30 mL), and concentrated in vacuo. The crudeproduct was purified by column chromatography (MTBE/heptane=1/10 to 1/5)to give the title compound (4.72 g, 83%). ¹H NMR (CDCl₃, 400 MHz): δ7.93 (m, 2H), 7.66 (m, 1H), 7.57 (m, 2H), 6.87 (dd, 1H), 6.71 (dd, 1H),4.19 (m, 1H), 3.93 (t, 1H), 3.63 (m, 1H), 3.28 (dd, 1H), 3.10 (dd, 1H),2.10 (m, 1H), 1.94 (m, 1H), 1.00 (t, 9H), 0.86 (d, 3H), 0.81 (d, 3H),0.64 (q, 6H).

(3R,4R,5S,6S,E)-4,6-dimethyl-1-(phenylsulfonyl)-5-((triethylsilyl)oxy)octa-1,7-dien-3-ol

To a cooled (0° C.) mixture of zinc (100 mesh, 2.8 g, 5.0 equiv), leaddichloride (0.24 g) and acetic acid (0.975 mL, 2 equiv) in water (8.4mL) was added a solution oftriethyl(((2S,3S,4R,5R,6R)-2-(iodomethyl)-3,5-dimethyl-6-((E)-2-(phenylsulfonyl)vinyl)tetrahydro-2H-pyran-4-yl)oxy)silane(4.72 g, 8.6 mmol) in tetrahydrofuran (43.7 mL). After stirring at 0° C.for 2 h, additional zinc (1 g, 1.8 equiv) was added and stirring wascontinued at 0° C. for 3 h and at rt for 12 h. Additional zinc (powder,1.4 g, 2.5 equiv) and acetic acid (0.15 mL, 0.3 equiv) were added andstirring was continued at rt for another 7 h. After removal of unreactedzinc by filtration, the filtrate was washed with saturated aqueousNaHCO3 (17 mL), and the aqueous layer was back-extracted with2-methoxy-2-methylpropane (50 mL). The organic layers were combined,washed with brine, and concentrated in vacuo. The crude product waspurified by column chromatography (MTBE/n-heptane=1/10 to 1/2) to givethe title compound (2.6 g, 71%). ¹H NMR (CDCl₃, 400 MHz): δ 7.92 (m,2H), 7.63 (m, 1H), 7.55 (m, 2H), 6.90 (dd, ii), 6.68 (dd, 1H), 5.80 (m,1H), 5.10 (m, 2H), 4.88 (4.19 (m, 1H), 3.80 (s, 1H), 3.70 (m, 1H), 2.50(m, 1H), 1.92 (m, 1H), 1.08 (d, 3H), 0.98 (t, 9H), 0.91 (d, 3H), 0.66(q, 6H).

(2S,3R,4R,5S,6S)-2,4,6-trimethyl-1-(phenylsulfonyl)oct-7-ene-3,5-diol

(3R,4R,5S,6S,E)-4,6-dimethyl-1-(phenylsulfonyl)-5-((triethylsilyl)oxy)octa-1,7-dien-3-ol(51 mg, 0.12 mmol) in tetrahydrofuran (2 mL) was cooled to −78° C. andtreated with 1.5 M methyllithium-lithium bromide complex in ether (0.24mL, 3.0 equiv). After stirring at −78 C˜−60° C. for 1 h, the mixture wastreated with chlorotrimethylsilane (46 μL, 3.0 equiv) and stirred at−60° C. for additional 20 min. After cooling back to −78° C., themixture was treated with 1.5 M methyllithium-lithium bromide complex inether (0.24 mL, 3.0 equiv) and warmed up to −40° C. over 3 h. Thereaction was quenched with sat.NH4Cl and extracted with MTBE. Theorganic layer was dried over MgSO4 and concentrated in vacuo.

The residue was dissolved in tetrahydrofuran (2 mL), treated with 1 Mtetra-n-butylammonium fluoride in tetrahydrofuran (0.36 mL), and stirredat rt for 1 h. After dilution with MTBE, the mixture was washed withwater and dried over MgSO4. The crude product was purified by columnchromatography (ethyl acetate/n-heptane=1/10 to 2/1) to give the titlecompound (7 mg, 20%). ¹H NMR (CDCl₃, 400 MHz): δ 7.95 (m, 2H), 7.70 (m,1H), 7.61 (m, 2H), 5.70 (m, 1H), 5.20 (m, 2H), 3.83 (dd, 1H), 3.32 (m,1H), 3.28 (dd, 1H), 3.23 (ds, 1H), 2.93 (dd, 1H), 2.40 (m, 1H), 2.26 (m,1H), 2.20 (bs, 1H), 1.70 (m, 1H), 1.19 (d, 3H), 1.02 (d, 3H), 0.94 (d,3H).

(2R,3R,4R,5S,6S)-2,4,6-trimethyl-1-(phenylsulfonyl)oct-7-ene-3,5-diol

To a cold (0° C.) suspension of copper(I) iodide (0.45 g, 5 equiv) intetrahydrofuran (10 mL) was added 1.6 M methyllithium in ether (4.42 mL,15 equiv). After stirring at 0° C. for 30 min, the mixture was treatedwith a solution of(3R,4R,5S,6S,E)-4,6-dimethyl-1-(phenylsulfonyl)-5-((triethylsilyl)oxy)octa-1,7-dien-3-ol(0.2 g, 0.47 mmol) in tetrahydrofuran (2 mL and 1 mL for rinse). Themixture was stirred at 0° C. for 1 h and at rt for 1 h. The reaction wasquenched with a mixture of 28% ammonium hydroxide (4 mL) and saturatedNH4Cl (40 mL), and the resulting mixture was extracted with MTBE. Theorganic layer was washed with brine and concentrated in vacuo. The crudeproduct was purified by column chromatography (ethylacetate/n-heptane=1/10 to 1/2) to give the title compound (95 mg, 62%).¹H NMR (CDCl₃, 400 MHz): δ 7.95 (m, 2H), 7.66 (m, 1H), 7.60 (m, 2H),5.70 (m, 1H), 5.20 (m, 2H), 3.50-3.70 (m, 2H), 3.37 (m, 1H), 2.90 (dd,1H), 2.40 (m, 1H), 2.28 (m, 1H), 1.90 (m, 1H), 1.15 (d, 3H), 1.01 (2d,6H).

F. Exemplary Elaboration of Protected Tetrad of Formula 3

The protected tetrad of Formula 3 was used to prepare intermediates ofaplyronine as described below.

(2S,3R,6S,7S,8R,9S,E)-2-((2R,3R,5S)-5-methoxy-3-methyltetrahydrofuran-2-yl)-6,8-dimethyl-11-(phenylsulfonyl)-7,9-bis((triethylsilyl)oxy)undec-4-en-3-ol

A mixture of(5S,6R,7S)-5-((S)-but-3-en-2-yl)-3,3,9,9-tetraethyl-6-methyl-7-(2-(phenylsulfonyl)ethyl)-4,8-dioxa-3,9-disilaundecane(84 mg, 0.16 mmol) and(3R,4S)-4-((2R,3R,5S)-5-methoxy-3-methyltetrahydrofuran-2-yl)pent-1-en-3-ol(21 mg, 0.11 mmol) was dissolved in a degassed 1,2-dichloroethane (3 mL)and heated to 45° C. After stirring at 45° C. for 5 min, the mixture wastreated with Grubbs 2^(nd) generation catalyst (6 mg, 7 μmol) andstirred at 45° C. for 21 h and at 60° C. for 2 h. The mixture was cooledto rt and concentrated in vacuo. The residue was purified by columnchromatography (ethyl acetate/n-heptane=1/10 to 2/1) to give the titlecompound (8 mg, 10%) along with 67% of recovered starting material. ¹HNMR (CDCl₃, 400 MHz): δ 7.95 (m, 2H), 7.70 (m, 1H), 7.61 (m, 2H), 5.76(dd, 1H), 5.49 (dd, 1H), 4.98 (d, 1H), 4.31 (M, 1H), 3.83 (bq, 1H), 3.59(dd, 1H), 3.52 (dd, 1H), 3.38 (s, 3H), 3.16 (m, 1H), 3.13 (d, 1H), 3.05(m, 1H), 2.32 (m, 2H), 2.13 (m, 1H), 1.90 (m, 2H), 1.83 (m, 1H), 1.65(m, 1H), 1.49 (m, 1H), 1.12 (d, 3H), 0.9-1.4 (m, 24H), 0.81 (d, 3H),0.62 (q, 6H), 0.56 (q, 6H).

(2S,3R,6S,7S,8R,9S)-2-((2R,3R,5S)-5-methoxy-3-methyltetrahydrofuran-2-yl)-6,8-dimethyl-11-(phenylsulfonyl)-7,9-bis((triethylsilyl)oxy)undecan-3-ol

(2S,3R,6S,7S,8R,9S,E)-2-((2R,3R,5S)-5-methoxy-3-methyltetrahydrofuran-2-yl)-6,8-dimethyl-11-(phenylsulfonyl)-7,9-bis((triethylsilyl)oxy)undec-4-en-3-ol(8 mg, 11 μmol) was dissolved in ethyl acetate (3 mL) and treated with10% Pd on C (5 mg). The mixture was stirred at rt under hydrogenatmosphere (balloon) for 1 h. The catalyst was filtered off and rinsedwith ethyl acetate. The filtrate was concentrated in vacuo to give thetitle compound in quantatative yield. ¹H NMR (CDCl₃, 400 MHz): δ 7.95(m, 2H), 7.69 (m, 1H), 7.61 (m, 2H), 4.95 (d, 1H), 3.84 (m, 2H), 3.60(dd, 1H), 3.45 (m, 1H), 3.37 (s, 3H), 3.35 (d, 1H), 3.03-3.22 (m, 2H),2.31 (m, 1H), 2.14 (m, 1H), 1.91 (m, 2H), 1.59-1.75 (m, 3H), 1.45-1.55(m, 4H), 1.35 (m, 1H), 1.09 (d, 3H), 0.85-1.00 (m, 24H), 0.81 (d, 3H),0.50-0.63 (m, 12H).

1. A compound of Formula 1′:

wherein: R is hydrogen or —C(O)R¹, and R¹ is selected from the groupconsisting of C₁-C₈alkyl, C₁-C₈alkenyl, aryl, and heteroaryl, R¹ may beunsubstituted or substituted from 1 to 3 times with independentlyselected C₁-C₆alkyl, hydroxy, hydroxyC₁-C₆alkyl, methoxy,methoxyC₁-C₆alkyl, halo, haloC₁-C₆alkyl, —C(O)NH₂, —NHCOOC₁-C₆alkyl, or—COOH group(s); or a salt thereof. 2-3. (canceled)
 4. The compound ofclaim 1 having the structure of Formula 1:

or a salt thereof.
 5. The compound of claim 4 having the stereochemistryof Formula 1A:

or a salt thereof.
 6. The compound of claim 4 having the stereochemistryof Formula 1B:

or a salt thereof.
 7. (canceled)
 8. The compound of claim 1 having thestructure of Formula 2:

or a salt thereof. 9-10. (canceled)
 11. A process for preparing compoundof claim 4, comprising the steps of: reacting6,8-dimethyl-3,9-dioxatricyclo[3.3.1.0^(2,4)]nonan-7-one with a reducingagent to form an intermediate having the following structure:

and reacting the intermediate with an acid to form the compound of claim4. 12-14. (canceled)
 15. A process for resolving enantiomers of thecompound of claim 4, comprising the steps of: reacting the racemiccompound of Formula 1 with phthalic anhydride to form a racemic mixtureof phthalates of Formulas 2A and 2B having the structure:

reacting the racemic mixture of phthalates of Formulas 2A and 2B with afirst chiral amine in a solvent to form a pair of diastereomeric saltsthereof in a solution; precipitating a first diastereomeric salt of thepair of diastereomeric salts from the solution to provide an isolatedfirst diastereomeric salt and an second diastereomeric salt; and formingthe enantiomers of the compound of Formula 1 from the isolated firstdiastereomeric salt and the second diastereomeric salt, therebyresolving the enantiomers of the compound of claim
 4. 16-19. (canceled)20. The process of claim 15, wherein the isolated first diastereomericsalt is treated with a base to form a first enantiomeric compound ofFormula
 1. 21. The process of claim 20, wherein the first enantiomericcompound of Formula 1 is the compound of Formula 1B:

or a salt thereof. 22-23. (canceled)
 24. The process of claim 15,further comprising the steps of: acidifying the second diastereomericsalt to form a free phthalate; reacting the free phthalate with a secondchiral amine to reform the second diastereomeric salt in a solution;precipitating the second diastereomeric salt from the solution to forman isolated second diastereomeric salt; and forming a secondenantiomeric compound of Formula 1 from the isolated seconddiastereomeric salt. 25-29. (canceled)
 30. The process of claim 24,wherein the second enantiomeric compound of Formula 1 is the compound ofFormula 1A


31. (canceled)
 32. A compound of Formula I:


33. The compound of claim 32 having the stereochemistry of the compoundof Formula Ia:


34. The compound of claim 32 having the stereochemistry of the compoundof Formula Ib:


35. A process for preparing compound of claim 32, comprising the stepsof: treating a compound of Formula 1 with an oxidizing agent to form thecompound of claim
 32. 36-37. (canceled)
 38. The process of claim 35,wherein the process forms an intermediate ketone having the followingstructure of Formula Ia″:


39. (canceled)
 40. The process of claim 35, wherein the process forms anintermediate ketone having the following structure of Formula Ib″:

41-43. (canceled)
 44. The process of claim 35, wherein the compound ofFormula 1 is a compound of Formula 1A:

and the compound of Formula I has the stereochemistry of a compound ofFormula Ia:


45. The process of claim 35, wherein the compound of Formula 1 is acompound of Formula 1B:

and the compound of Formula I has the stereochemistry of a compound ofFormula Ib:

46-56. (canceled)
 57. A method of preparing a therapeutic, comprisingreacting a compound having a structure of:

wherein: Ph is phenyl; R³ is each independently a hydrogen or an oxygenprotecting group; or salt thereof, and preparing a therapeutic.